Role of circulating tumor cells as prognostic marker in resected stage III colorectal cancer.

BACKGROUND: The prognostic role of circulating tumor cells (CTC) in early colorectal cancer (CRC) has not been determined yet. We evaluated the potential prognostic value of CTC in stage III CRC patients. PATIENTS AND METHODS: Prospective multicenter study of 519 patients with stage III CRC recruited between January 2009 and June 2010. CTC were enumerated with the CellSearch System after primary tumor resection and before the start of adjuvant therapy. A total of 472 patients were included in the analysis. RESULTS: CTC ≥1, ≥2, ≥3 and ≥5 were detected in 166 (35%), 93 (20%), 57 (12%) and 34 (7%) patients, respectively. Median follow-up was 40 months. In the overall population, CTC ≥1 (disease-free survival (DFS): HR 0.97, P = 0.85; overall survival (OS): HR 1.03, P = 0.89), ≥2 (DFS: HR 1.07, P = 0.76; OS: HR 1.02, P = 0.95), ≥3 (DFS: HR 0.96, P = 0.87; OS: HR 0.74, P = 0.41) and ≥5 (DFS: HR 0.72, P = 0.39; OS: HR 0.48, P = 0.21) were not associated with worse DFS and OS. No clinicopathological characteristics were significantly associated with the presence of CTC. In patients with disease relapse, the proportion with CTC ≥1 was not significantly different between those with single versus multiple metastatic locations (37.9% versus 31.4%, P = 0.761). In the multivariate analysis, CTC ≥1 was not an independent prognostic factor for DFS (HR 0.97, P = 0.87) and OS (HR 0.96, P = 0.89). CONCLUSION: CTC detection was not associated with worse DFS and OS in patients with stage III CRC. Given the scarcity of CTC in these patients, it is likely that CTC determined by CellSearch system does not have a prognostic role in this setting. However, a longer follow-up is needed.

Combined methylation of p16 and hMLH1 (CMETH2) discriminates a subpopulation with better prognosis in colorectal cancer patients with microsatellite instability tumors.

The aim of this study was to determine the frequency of p16 and hMLH1 genes simultaneous methylation in colorectal cancer patients with Microsatellite Instability (MSI) tumors. We also wanted to analyze the relationship with other clinical features, with BRAF gene V600E mutation and with prognosis. Samples from fifty one patients with MSI positive sporadic colorectal cancer were included. DNA was extracted from tumor samples. Promoter methylation was analyzed using bisulfite modification and was detected by quantitative methylation-specific PCR. BRAF gene was amplified using specific primers and mutations were detected by real time PCR. Simultaneous methylation was transformed in a new variable called CMETH2. Frequency of CMETH2 was analyzed and compared with other clinicopathological variables. 33.3 % of patients were positive for CMETH2 and 25 % had BRAF V600E mutation. CMETH2 was related with proximal location, with poorly differentiated tumors and with BRAF V600E mutation. CMETH2 only showed influence in the overall survival (OS) in patients with distal tumors. However, with regard to the disease free survival (DFS) measure, CMETH2 was independent prognostic factor. We were able to discriminate tumors with high methylation features using a transformation analysis of variables into a new computed one (CMETH2). CMETH2 has demonstrated to be a useful prognostic factor in MSI tumors. The prognostic value of CMETH2 in DFS was independent of other clinicopathological variables. The use of CMETH2 could help in the election of the best therapeutic alternative for CCR patients with MSI tumors.

Circulating tumor cells in colorectal cancer: correlation with clinical and pathological variables.

BACKGROUND: The CellSearch System is a technique to detect circulating tumor cells (CTCs) in patients with cancer. Few data have been published concerning the role of CTCs detection by this method in colorectal cancer. The aim of this study was to correlate the presence of CTCs with the commonest clinical and morphological variables. PATIENTS AND METHODS: Blood samples were collected from 97 patients and 30 healthy volunteers. Quantification of CTCs in 7.5 ml of blood was carried out with the CellSearch System. The results were expressed as number of CTCs/7.5 ml and the cut-off of >or=2 CTCs/7.5 ml was chosen to define the test as positive. RESULTS: Positive CTCs were detected in 34 of 94 patients (36.2%). Correlation was not found among positive CTCs and location of primary tumor, increased carcinoembryonic antigen level, increased lactate dehydrogenase level or grade of differentiation. Only stage correlated with positive CTCs (20.7% in stage II, 24.1% in stage III and 60.7% in stage IV, P = 0.005). CONCLUSIONS: CTCs detection by CellSearch is a highly reproducible method that correlates with stage but not with other clinical and morphological variables in patients with colorectal cancer. Colon cancer tumor cells are detectable in all stages. Further studies are warranted.

Telomerase activity in colorectal cancer, prognostic factor and implications in the microsatellite instability pathway.

AIM: To determine whether the telomerase activity is related to the Microsatellite instability (MSI) genetic pathway and whether it means a difference in the survival. METHODS: The population consisted of 97 colorectal cancer patients. MSI determination was performed in accordance with the NCI criteria using PCR and Genescan. Telomerase activity was determined by the TRAP-assay, an ELISA procedure based on the amplification of telomeric repeat sequences. RESULTS: 6.2% showed high MSI (MSI-H), 10.3% showed low MSI (MSI-L) and 83.5% did not show this alteration (MSS). Positive telomerase activity was detected in 92.8% of the patients. 83.3% of MSI-H tumors showed positive telomerase against 93.8% of MSS tumors. In the overall survival analysis the absence of telomerase activity conferred a better prognosis. CONCLUSION: Previous works have shown that tumors which develop via the MSI pathway present a better prognosis. No link between telomerase activity and MSI status is observed, although sample sizes are small. Patients with telomerase negative tumors had better overall survival than patients with telomerase positive tumors.

Effects of pork vs veal consumption on serum lipids in healthy subjects.

AIMS: To analyse the influence of lean pork (P) and veal (V) consumption on the lipid profile of healthy subjects within the framework of a healthy diet comprising low levels of total fat (TF), saturated fatty acids (SFA) and cholesterol. DESIGN: Double-crossover, randomized and controlled trial SUBJECTS: 44 healthy individuals (22 male and 22 female), recruited voluntarily from the University Complutense of Madrid. The weight and lipid profiles of these volunteers were normal and their dietary patterns were typical for people in our area. INTERVENTIONS: The study comprised 4 phases: stabilisation phase (5 weeks), the participants followed their normal diet; second phase (6 weeks), half of the subjects, were randomised to lean pork or veal consumption, 150 g per day, for their main meal of the day; washout period (5 weeks) and final phase, which was the second phase of intervention (6 weeks). During the intervention stages, only the main meal of the day was taken in the Hospital. The rest of the subjects' diets consisted of different fortnightly menus designed in accordance with the recommendations of the Spanish Society of Arteriosclerosis (SEA). RESULTS: After both stages of intervention had been completed, there was a mean reduction of 5.5% in low-density lipoprotein cholesterol. However, after each intervention there were no significant differences between those who had consumed P, 2.62 (0.55) mmol/L and those who had consumed V, 2.71 (0.47) mmol/L. No differences were observed in any of the other parameters between those who had consumed P and those who had consumed V. CONCLUSIONS: Lean pork and veal produces similar effects on the lipid profiles of healthy subjects. Its consumption, as part of the saturated fat and cholesterol-controlled diet, could therefore be included in food guidelines, both for normal and therapeutic diets.

Prognostic value of the quantified expression of p185 in non-small cell lung cancer.

BACKGROUND: We sought to assess the relationship between tissue concentration of erb -b-2 or neu oncogene-encoded protein (p185(neu)) with overall survival in patients with non-small cell lung cancer. METHODS: Levels of protein p185(neu) were determined in 102 patients with the diagnosis of non-small cell lung cancer. Concentration of p185(neu) protein was determined by using enzyme immunoassay and evaluated by using several variables. The relative prognostic importance of this marker and its influence on other prognostic factors was evaluated by using the Cox regression model. RESULTS: The mean p185(neu) value in these samples was 250 +/- 200 U/mg (95% confidence interval, 210-290). This distinguished two groups within the tumoral population: those with less than 350 U/mg and those with 350 U/mg or greater (80th percentile). Multivariable analysis established an independent prognostic value for protein p185(neu). Patients with p185(neu) values of the 80th percentile or greater had a risk of death that was 2.11-fold (95% confidence interval, 1.10-4.05) that of patients with values of less than 350 U/mg (P =.03), and increases in the neu oncogene of 100 U/mg increased the probability of death by 17% (P =.02; 95% confidence interval, 1.04-1.31). CONCLUSION: This study shows that the p185(neu) expression is an objective and comparable variable for the assessment of phenotypic aggressivity in non-small cell lung cancer, and in the future, it could be included in daily clinical practice.

Prognostic significance of p53 gene mutations in squamous cell carcinoma of the lung.

The aim of the present study was to analyze the prevalence and clinical importance of p53 gene mutations in surgically treated squamous cell lung carcinoma. Sixty patients were included. Fifty-one patients in stages I to IIIa were submitted to radical resection. Twenty-five samples tested positive for the p53 immunohistochemistry assay, and were analyzed for p53 gene mutations. Eleven mutations were found. Patients harboring p53 gene mutations suffered a higher incidence of recurrence and a higher mortality rate. Disease-free interval and overall survival were shorter for patients with mutated p53 gene (p=0.03 and p=0.005, respectively).

Prognostic significance of preoperative serum CA 19.9 assay in patients with colorectal carcinoma.

The prognostic information provided by preoperative serum CEA and CA 19.9 antigen assay on the postoperative outcome of 150 patients with colorectal cancer was analysed. The influence of both markers was studied by Cox's proportional-hazard regression analysis. In the univariate analysis, patients whose initial CA 19.9 level was higher than 37 U/ml had a 4.32-fold greater risk of death due to the cancer (95% CI: 1.72-10.84) (p < 0.001) than patients with lower values. The 36-month survival rate posttreatment was lower for patients with CA 19.9 serum levels over 37 U/ml (61% versus 90%) (p < 0.001). Patients whose initial CEA level was higher than 5 ng/ml had a 2.9-fold greater risk of death (95% CI: 1.05-7.99) (p = 0.04) than patients with lower values. The 36-month survival rate posttreatment was lower for patients with CEA serum levels over 5 ng/ml (84% versus 76%) (p = 0.04). After adjustment for Dukes' stage, CEA, CA 19.9, tumor site, sex and age, only Dukes' stage and CA 19.9 continued to provide independent predictive information on survival. The risk of death increases by 1.008 for every 10 U/ml rise in the level of the marker (95% CI: 1.002-1.014) (p = 0.009). With respect to analysis of disease-free survival, only Dukes' stage provided independent predictive value. CA 19.9 is an independent prognostic factor of survival in colorectal cancer. The authors suggest including CA 19.9 in a future multifactorial analysis of survival.

Concordance between serum and cytosolic levels of CEA, CA125 and SCC antigens in patients with non-small cell lung cancer.

The relationship between serum and cytosolic levels of carcinoembryonic (CEA), squamous-cell carcinoma (SCC) and CA125 antigens was determined in 122 patients with non-small cell lung cancer. A pronounced serum-cytosol gradient and a high degree of dispersion in the distribution of serum and cytosol marker concentrations was detected. In addition, the degree of concordance between TM levels in the two compartments, determined by the intraclass correlation coefficient (ICC) index, was low (ICC = 0.42 for CEA; 0.35 for CA 125; and 0.27 for SCC). Tumour stage and histological type both played a limited role in the serum-cytosol relationship. As tumour stage advanced, the concordance between serum and cytosolic TM level became more pronounced. In addition, each histological type showed a distinctive pattern of expression of serum and cytosolic tumour markers, and a specific degree of concordance between levels in serum and cytosol. However, the ICC indices were always under 0.51, indicating that the importance of these factors is minor. The data obtained indicate that the relationship between serum and cytosolic concentration is moderate. The differences found according to stage grouping and histological subtype are so small that no clear-cut message for clinical practice can be drawn.

Role of microsatellite instability in borderline ovarian tumors.

This study was designed to establish the role of microsatellite instability (MSI) in the development of sporadic tumors of the ovary. The instability of 6 microsatellites (BAT25, BAT26, NME1, D17S250, D5S346 and D2S123) was determined by comparing MSI in healthy and tumoral tissue in each of 40 patients undergoing surgery for a sporadic ovarian tumor. BAT26 and D2S123 instability was detected in borderline tumors, and ovarian carcinomas were found to present instability in the microsatellites BAT25, NME1 and D17S250. Our findings indicate that microsatellite instability lacks a significant role in the appearance or progression of sporadic ovarian tumors.

Serum CEA, CA125, and SCC antigens and tumor recurrence in resectable non-small cell lung cancer.

Carcinoembryonic antigen (CEA), squamous cell carcinoma antigen (SCC), and CA125 were determined pre- and postoperatively in non-small cell lung cancer patients (NSCLC) to assess the relationship between serum levels and postoperative recurrent disease. Ninety-five patients who underwent curative surgical resection were included (TNM stages I, II, IIIa). CEA and CA125 were determined by solid-phase enzyme-immunoassay, SCC by radio-immunoassay. Tumor relapse was detected in 41 patients (43%): 16 (39%) with locoregional disease and 25 (61%) with disseminated disease. The overall 36-month disease-free survival rate was 42%. The sensitivity for recurrence was 58% for CEA, 53.6% for CA125, and 51.2% for SCC; 87.8% of patients showed at least one elevated marker. The sensitivity of CEA and CA125 increased significantly in patients with preoperative serum concentrations above the cut-off: 86.6% versus 42.3% (p < 0.01), and 93% versus 18% (p < 0.01), respectively. Preoperative CA125 above 15 U/ml identified a high-risk group of patients: a lower 36-month disease-free survival rate (0% versus 56%) (p < 0.001), a 3.02-fold higher risk of recurrence (p < 0.05), and a 6.22-fold higher risk of disseminated failure (p < 0.001). The identification of CEA and CA125 producer-tumors, based on preoperative serum values, enhances the clinical performance of a postoperative surveillance program in surgically treated NSCLC. Preoperative serum CA125 is a prognostic factor to identify patients at high risk of postoperative tumor recurrence.

Tissue quantification of CA 125 in epithelial ovarian cancer.

The objectives of this study were the determination of CA 125 in the cytosol of healthy and carcinomatous ovarian tissue by immunoanalysis, analysis of its correlation with the biological characteristics of ovarian carcinoma, determination of serum CA 125 levels, and study of the prognostic value of the marker in cytosol. The levels of the marker depend not only on the tumor's production rate, so its determination in tissue can indicate more accurately if the tumor is a producer of the marker and establish its value for the prognosis of the disease. Determination of CA 125 in tissue was performed by immunoanalysis in 50 ovarian epithelial cancer samples, 13 benign pathology samples and 32 healthy ovary samples. The presurgical serum level of the marker was also obtained. The correlation between the CA 125 level in the cytosol and the different biological characteristics of the ovarian carcinoma, the serum levels of the marker and survival were analyzed. The CA 125 level proved to be higher in malignant tissue (p < 0.0001). There was a significant association between the tissue marker and histological type (high CA 125 was associated with serous and endometrioid tumors) and between the marker and survival. No relation with stage was found. There was a correlation between the CA 125 level in the cytosol and serum both variables being dependent, with a correlation coefficient of 0.44. This good correlation speaks in favor of the usefulness of CA 125 determination in serum in the follow-up of ovarian cancer. Tumors having high tissue expression of CA 125 were found to have a double relative risk of death, independently of tumor stage.

Tumor markers in pancreatic cancer: a comparative clinical study between CEA, CA 19-9 and CA 50.

Seventy-eight patients were evaluated to ascertain the usefulness of markers CA 19-9 and CA 50 in diagnosing pancreatic cancer, using a less specific marker (CEA) as reference. Three groups were considered: a) 36 controls; b) 22 patients with benign obstructive jaundice; c) 20 patients with pancreatic cancer. Preoperative blood samples were obtained to ascertain CEA (E.I.A.), CA 19-9 (R.I.A.) and CA 50 (T.R.-F.I.A.). Serum concentrations of the various markers were significantly higher for patients with pancreatic cancer in comparison with the other groups, at cut-offs of 10 ng/ml (CEA), 100 ng/ml (CA 19-9) and 170 U/ml (CA 50). The sensitivity of CA 19-9 (94%) and CA 50 (88%) was much greater than that of CEA (30%). The specificity of the three markers in patients with pancreatic cancer, with respect to the control group, was 100% and this figure is reduced with respect to the group suffering from benign obstructive jaundice (CEA: 90%; CA 19-9: 88% and CA 50: 87%). Diagnostic results (sensitivity, specificity, positive predictive value (P.P.V.) and negative predictive value (N.P.V.] did not significantly increase with respect to CA 19-9 and CA 50 when considered individually. It is concluded that the serum concentrations of CA 19-9 and CA 50 showed high sensitivity and specificity as markers of pancreatic cancer with respect to the other groups, pointing towards clinical routine clinical use of both markers. In addition, a comparative study of the literature has been made and prospects for short-term development and concrete applications for early and reliable diagnosis have been highlighted.

[Epidermal growth factor receptor in non-small cell cancer of the lung]. / Receptor para el factor de crecimiento epidérmico en el cáncer de pulmón no microcítico.

In this study we determined the concentration of epidermic growth factor receptors (EGFr) in non-small cell carcinoma of the lung (NSCCL) and analyzed its relation to the anatomical, pathological and clinical factors of these neoplasms. The concentration of EGFr in 62 tumor tissue samples was 9.9 +/- 14 fmol/mg, higher than that found in 14 tissue samples from cases of spontaneous pneumothorax (3.9 +/- 3.6 fmol/mg) (p = 0.005). EGFr concentration in lung tissue with no signs of neoplasm was 6.5 +/- 10 fmol/mg. In 21 (33%) cases of NSCCL the concentration exceeded the normal threshold of 10 fmol/mg. EGFr concentration was higher in cases of epidermoid carcinoma than in other tissue samples (p = 0.042). No significant association was found between EGFr levels and status of tumor node metastasis, degree of differentiation and mitotic index. The probability of remaining free of tumor recurrence and of survival after 24 months among patients whose tumoral EGFr concentration was below 10 fmol/mg was 34 and 40%, respectively. The rates for patients with concentrations that exceeded the threshold were 20% (p = 0.32) and 25% (p = 0.26), respectively. The results seem to indicate that the study of EGFr concentration alone does not yield practically important information for the management of patients with NSCCL who have undergone surgery. The concentration of EGFr marks degree of differentiation in NSCCL and has prognostic implications derived from its association with other factors.

[Prognostic value of heterozygosity loss in chromosome 3p in non-microcytic bronchogenic carcinoma]. / Valor pronóstico de la pérdida de heterozigosidad en el cromosoma 3p en el carcinoma broncogénico no microcítico.

BACKGROUND: Recent advances on carcinogenesis have led to the recognition of different patterns of behaviour of non-small cell lung cancers apart from those guided by the TNM staging system and the histologic subtype. The frequent genetic loss on chromosome 3p in all kinds of lung carcinoma leads to the suspect of the presence of a tumor suppressor gene located in that place. The aim of this work was to compare the different clinical features and evolution after treatment of the patients with non small cell lung carcinoma with and without loss of heterozygosity (LOH) on 3p. PATIENTS AND METHOD: Forty-five operated on non-small cell lung cancer patients were evaluated. The mean age was 64.4 years and all the patients were male. Seven patients had been previously treated for another epithelial neoplasm. 82.2% of the patients were heavy tobacco smokers. Most of the tumors (62.2%) were squamous cell carcinomas. Samples of tumoral and non tumoral lung tissue were immediately frozen after surgery. DNA from the tissue was extracted; then PCR amplification of microsatellites in regions 3p14 and 3p21 was performed. To determine the LOH in the regions analyzed a polyacrylamide gel electrophoresis was performed. RESULTS: Twenty-five percent of the informative samples for 3p14 and 21.9% for 3p21 showed LOH. There was an statistical relationship between the LOH on 3p14 and the history of tobacco smoking and the adenocarcinoma histologic subtype (p < 0.05). There was a higher number of relapses and a shorter disease-free interval in those patients harboring 3p21 LOH. CONCLUSIONS: LOH on 3p can be detected in non-small cell lung carcinoma. Patients with loss of heterozygosity on 3p21 have a worse evolution after a curative intended surgical resection.

Prognostic significance of the p185 protein in colorectal cancer.

The amplification and/or overexpression of the c-erbB-2/neu oncogene may play a role in tumor development and progression. The aim of this prospective study was to evaluate the prognostic value of p185 protein in colorectal cancer using immunohistochemical techniques. We analyzed 106 colorectal tumor tissue specimens from patients who had been operated on by the same surgeon and subjected to a median follow-up of 3 years. Thirty-three per cent of patients showed p185 overexpression related to an advanced stage of the disease. In patients with adenocarcinoma tumors of the colon without distant metastases, p185 detection was found to be of clinical prognostic relevance (p = 0.06).

Diagnostic and predictive value of urine PCA3 gene expression for the clinical management of patients with altered prostatic specific antigen.

OBJECTIVE: Analyze the impact of the introduction of the study of PCA3 gene in post-prostatic massage urine in the clinical management of patients with PSA altered, evaluating its diagnostic ability and predictive value of tumor aggressiveness. METHODS: Observational, prospective, multicenter study of patients with suspected prostate cancer (PC) candidates for biopsy. We present a series of 670 consecutive samples of urine collected post-prostatic massage for three years in which we determined the "PCA3 score" (s-PCA3). Biopsy was only indicated in cases with s-positive PCA3. RESULTS: The s-PCA3 was positive in 43.7% of samples. In the 124 biopsies performed, the incidence of PC or atypical small acinar proliferation was 54%, reaching 68,6% in s-PCA3≥100. Statistically significant relationship between the s-PCA3 and tumor grade was demonstrated. In cases with s-PCA3 between 35 and 50 only 23% of PC were high grade (Gleason≥7), compared to 76.7% in cases with s-PCA3 over 50. There was a statistically significant correlation between s-PCA3 and cylinders affected. Both relationships were confirmed by applying a log-linear model. CONCLUSIONS: The incorporation of PCA3 can avoid the need for biopsies in 54% of patients. s-PCA3 positivity increases the likelihood of a positive biopsy, especially in higher s-PCA3 100 (68.6%). s-PCA3 is also an indicator of tumor aggressiveness and provides essential information in making treatment decisions.

Role of fibroblast growth factor 23 (FGF23) in the metabolism of phosphorus and calcium immediately after kidney transplantation.

INTRODUCTION: Persistence of inappropriately high serum levels of fibroblast growth factor-23 (FGF23), a recently discovered phosphaturic hormone, has been reported to play an important role in the pathogenesis of posttransplant hypophosphatemia. The aim of the present study was to evaluate FGF23 in the early posttransplant period and study the complex associations between FGF23, parathyroid hormone (PTH), 1,25(OH)(2) vitamin D, and phosphate in transplant patients. MATERIALS AND METHODS: We performed a cross-sectional observational study of 42 adult kidney recipients in the early posttransplant period (<6 months). Fasting serum samples and 24-hour urine samples were collected during a routine follow-up outpatient visit. Serum creatinine, calcium, phosphate, magnesium and urinary creatinine, calcium, magnesium, and phosphate were measured using standard assays. We also studied concentrations of 25 hydroxyvitamin D, 1,25(OH)(2) vitamin D, intact PTH, and circulating FGF23. RESULTS: Median values for the different parameters studied were as follows: 9.9 ± 0.6 mg/dL, phosphatemia 3.3 ± 0.7 mg/dL, estimated glomerular filtration rate (eGFR; 41.1 ± 14.0 mL/min, phosphate reabsorption rate 68.4% ± 10.7%, PTH 94.5 ng/L (53.8-199.5), calcitriol 33.0 pg/mL (24.0-44.1), calcidiol 27.3 ng/mL (17.0-38.0), FGF23 139 pg/mL (88-221), and calciuria 62.5 mg/d (40.3-101.3). The variables significantly associated with serum FGF23 levels were phosphate reabsorption rate (r = .493; P = .001), calcitriol (r = .399; P = .009), eGFR (r = .557; P < .001), PTH (0.349; P = .024). CONCLUSIONS: Elevated serum levels of FGF23 could explain the deficiency of calcitriol and elevated renal phosphorus wasting in the early posttransplant period. All treatments that can lead to increased serum phosphate levels (eg, oral medication or calcitriol) should be carefully evaluated, since increased phosphatemia could further stimulate secretion of FGF23 and prolong high phosphorus loss.

The prevalence of uridine diphosphate-glucuronosyltransferase 1A9 (UGT1A9) gene promoter region single-nucleotide polymorphisms T-275A and C-2152T and its influence on mycophenolic acid pharmacokinetics in stable renal transplant patients.

UNLABELLED: The aim of this study was to evaluate the distribution of UGT1A9 promoter region T-275A and C-2152T single nucleotide polymorphisms (SNPs) in stable transplant patients and to investigate the impact of these SNPs on mycophenolic acid (MPA) pharmacokinetics. METHODS: In total, 133 Caucasian renal transplant recipients were studied. Also a complete 12-hour pharmacokinetic profile was recorded for 15 transplant patients who had the polymorphism and for 15 controls who were randomly chosen since they received the same type and dosage of mycophenolate, same posttransplant time and similar renal function. RESULTS: The T-275A promoter mutation was detected in 12.03% of patients and the C-2152T in 9.77%. All patients with the mutation C-2152T had associated the mutation T-275A. Patients who carried either the T-275A or the C-2152T polymorphism (or both) experienced more admissions owing to gastrointestinal side effects (P < .05). The pharmacokinetics studies showed that carriers of T-275A and/or C-2152T displayed a smaller area under-concentration time curve (AUC): 57.8 +/- 4.3 vs 78.9 +/- 10.8 mg/L*h (P < .03). CONCLUSION: It seemed that carriers of T-275A and C-2152T SNPs of the UGT1A9 gene promoter region in the late posttransplant recipient group, showed a greater incidence of gastrointestinal side effects and a lower MPA exposure.

Colorectal carcinoma prognosis can be predicted by alterations in gene p53 exons 5 and 8.

BACKGROUND AND AIMS: Gene p53 alteration is a genetic event described in the progression from adenoma to colorectal carcinoma. Most of the p53 mutations occur in exons 5 to 8 in highly preserved regions and in the three main structural domains of the p53 protein. It is possible that mutations affecting different structural regions may present different effects on the p53 protein function and, due to this, they may have different prognostic meaning. MATERIALS AND METHODS: The study population consisted of 353 patients diagnosed with sporadic colorectal cancer. Mutations in 5-8 exons of p53 gene were detected by means of single strand conformation polymorphism (SSCP). All samples that showed different migration bands in SSCP were confirmed by sequencing. RESULTS: A total of 69 patients (19.7%) showed alterations of the gene p53. It was observed that mutation in codon 175 in exon 5 was related to tumors located in the colon (p = 0.01) and the mutation in the codon 288 in exon 8 was related to rectal tumors (p = 0.02). In the study of overall survival, mutation in codon 175 of exon 5 conferred a better prognosis and alterations of exon 8 were related to a worse prognosis in different population subgroups: in men, in patients younger than 71 years old, in the tumors located in the proximal colon, the ones moderately differentiated, and those that are mucinous. CONCLUSION: According to this study, mutations in different exons of p53 are related to different phenotypes in colorectal cancer. These phenotypes could mean differences in the clinical evolution of the patients.