ARMS2 A69S polymorphism is associated with the number of ranibizumab injections needed for exudative age-related macular degeneration in a pro re nata regimen during 4 years of follow-up.

PURPOSE: To investigate whether single-nucleotide polymorphisms (SNPs) known to be strongly associated with the development of age-related macular degeneration (AMD) have an influence on recurrence rate of choroidal neovascularization (CNV) activity during 4-year ranibizumab treatment for exudative AMD. METHODS: This prospective study included 103 treatment-naïve patients (103 eyes) that received initially a loading dose of 3 monthly ranibizumab injections and thereafter, were treated according to an as-needed regimen for a 4-year follow-up period. Baseline values, visual outcome, and recurrence rate were examined. CFH Y402H and ARMS2 A69S polymorphisms were determined and their association with lesion recurrence and visual outcome was analyzed using a one-way analysis of variance (ANOVA) with post hoc comparison tested by Fisher's LSD method. Multivariate linear regression analysis was then used to identify factors associated with recurrence rate. RESULTS: The cumulative total mean number of ranibizumab injections at the end of each year of the follow-up was 5.3 ± 1.8, 9.2 ± 2.9, 12.6 ± 4.6, and 15.7 ± 6.1. There was great inter-patient variability. Nineteen eyes (18.5%) did not experience recurrence during the first year, and five (4.8%) still displayed inactive CNV after 4 years of follow-up. No significant association was found between the number of injections and mean best corrected visual acuity (BCVA) change or final BCVA at the end of the study period. Genotypes had no influence on baseline characteristics or visual outcome but a significant association was found between the A69S polymorphism and the number of injections needed by the patients. Homozygous for the T risk allele required more retreatments over the 48-month follow-up. CONCLUSIONS: The ARMS2 A69S polymorphism was associated with CNV recurrence rate in our patient cohort. Prediction of a greater risk of recurrence could help to design more appropriate follow-up treatment strategies for patients with neovascular AMD.

Vascular Endothelial Growth Factor (VEGF) Polymorphisms and Serum VEGF Levels in Women With Epithelial Ovarian Cancer, Benign Tumors, and Healthy Ovaries.

OBJECTIVE: This study analyzed the relation of 5 single-nucleotide polymorphisms (SNPs) in the VEGF (vascular endothelial growth factor) gene in patients with epithelial ovarian cancer (EOC), compared with patients carrying benign tumors or healthy ovaries. We studied serum VEGF levels and the relation with SNPs and association between VEGF SNPs and haplotypes with progression-free survival (PFS) in patients with cancer. METHODS: The genotyping of VEGF gene polymorphisms (-2578 C/A, -1154 G/A, -460 T/C, +405 G/C, +936 C/T) was performed in DNA isolated from blood samples of 100 women. The different genotypes were evaluated by quantitative real-time polymerase chain reaction. Vascular endothelial growth factor protein concentration was assessed in serum using solid-phase sandwich enzyme-linked immunosorbent assay. RESULTS: We found statistically significant differences in the distribution of VEGF genotypes among the 3 groups of patients: -2578 C/A between those with EOC and healthy ovary (P = 0.04), -460 T/C between those with EOC and healthy ovary (P = 0.03), and -460 T/C between those with benign tumors and healthy ovary (P = 0.02). Vascular endothelial growth factor serum levels were analyzed in patients with EOC. Higher levels were found in patients with clear cell carcinoma compared with those with serous, mucinous, or endometrioid tumors (P < 0.05). No clear association was observed between VEGF SNPs and serum VEGF levels. There was no significant correlation between VEGF SNPs and PFS. In haplotype analysis, CGTCT and CGTGT showed worse prognosis without reaching the statistical significance. CGCGC and AGTGC haplotypes had statistically significant differences among patients with EOC, benign tumors, and healthy ovaries (Ps = 0.046 and 0.041, respectively). CONCLUSIONS: The distribution of VEGF genotypes was different in patients with EOC, compared with those with benign tumors or women with healthy ovaries. Vascular endothelial growth factor serum levels were higher in patients with clear cell carcinoma. No correlation was found with improved PFS, but CGTCT and CGTGT haplotypes showed worse prognosis.

Bladder carcinoma data with clinical risk factors and molecular markers: a cluster analysis.

Bladder cancer occurs in the epithelial lining of the urinary bladder and is amongst the most common types of cancer in humans, killing thousands of people a year. This paper is based on the hypothesis that the use of clinical and histopathological data together with information about the concentration of various molecular markers in patients is useful for the prediction of outcomes and the design of treatments of nonmuscle invasive bladder carcinoma (NMIBC). A population of 45 patients with a new diagnosis of NMIBC was selected. Patients with benign prostatic hyperplasia (BPH), muscle invasive bladder carcinoma (MIBC), carcinoma in situ (CIS), and NMIBC recurrent tumors were not included due to their different clinical behavior. Clinical history was obtained by means of anamnesis and physical examination, and preoperative imaging and urine cytology were carried out for all patients. Then, patients underwent conventional transurethral resection (TURBT) and some proteomic analyses quantified the biomarkers (p53, neu, and EGFR). A postoperative follow-up was performed to detect relapse and progression. Clusterings were performed to find groups with clinical, molecular markers, histopathological prognostic factors, and statistics about recurrence, progression, and overall survival of patients with NMIBC. Four groups were found according to tumor sizes, risk of relapse or progression, and biological behavior. Outlier patients were also detected and categorized according to their clinical characters and biological behavior.

Association of biomarkers of inflammation, cartilage and bone turnover with gender, disease activity, radiological damage and sacroiliitis by magnetic resonance imaging in patients with early spondyloarthritis.

To assess the association between biomarkers of inflammation, cartilage and bone turnover with gender, Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), Spondylitis Disease Activity Score (ASDAS) and bone marrow oedema in resonance magnetic imaging (MRI) of sacroiliac joints (SIJs) and radiological damage in early spondyloarthritis (SpA). Cross-sectional study of 60 patients (56.7 % females; mean age, 32.4 years) with early SpA. Sociodemographic data, clinical features, serum matrix metalloproteinase 3 (MMP-3), high sensitivity C-reactive protein (hsCRP), C-terminal cross-linking telopeptides of type I collagen (CTX-I) and urinary deoxypyridinoline, ASDAS, BASDAI, BASFI, BASRI and MRI of the SIJs were collected. The mean (SD) disease duration was 12.4 (6.8 months). Twenty-two (68.7 %) of the 32 patients had active sacroiliitis by MRI. MMP-3 and CTX I correlated with swollen joint (r = 0.515, r = 0.386, p = 0.01). hsCRP correlated with ESR (r = 0.303, p = 0.05), with CRP (r = 0.455, p = 0.01) and with total BASRI (r = 0.95, p = 0.05). Biomarkers were unrelated with the rest of variables. Levels of MMP-3 (44.3 ± 52.4 vs 24.7 ± 33.4, p < 0.05) and CTX-I (0.53 ± 0.45 vs 0.24 ± 0.38; p < 0.05) were higher in men. Our study shows that CTX-I and MMP-3 are a marker of peripheral disease activity in early SpA. Male gender had higher levels of CTX-I and MMP-3, which may indicate higher disease activity. Higher hsCRP levels trended towards correlation with more baseline radiographic damage. Therefore, these biomarkers may help identify a subgroup of patients who will need closer monitoring and more intensive treatment.

Circulating tumor cells following first chemotherapy cycle: an early and strong predictor of outcome in patients with metastatic breast cancer.

We investigated the prognostic significance of circulating tumor cells (CTCs) determined immediately before the second cycle of chemotherapy in patients with metastatic breast cancer (MBC). The CTC counts were taken at baseline, before the first cycle of chemotherapy (CTC-0), and on day 21 before commencing the second cycle of chemotherapy (CTC-21) in consecutive MBC patients. The study's primary objectives were to analyze relationships between CTC-21 count and overall survival (OS). Based on the current literature, the CTC measurements were dichotomized as 0-4 versus ≥ 5 CTCs. Of 117 patients recruited, 99 were evaluable. Patients with 0-4 CTCs on day 21 had a significantly better OS than those with ≥ 5 CTCs (median OS: 38.5 months vs. 8.7 months). They also had a significantly better progression-free survival (PFS; median: 9.4 months vs. 3.0 months) and clinical benefit rate (77% vs. 44%). The OS of patients whose baseline CTCs were ≥ 5 but dropped to <5 on day 21 was apparently similar to those who had <5 CTCs at baseline. In a Cox regression analysis, CTC-21 was the only independent variable significantly predicting OS and PFS. Our data indicate that CTCs determined immediately before the second cycle of chemotherapy is an early and strong predictor of treatment outcome in MBC patients.

p16 gene methylation in colorectal cancer patients with long-term follow-up.

INTRODUCTION: p16 gene plays an important role in the cell cycle regulation and is considered an important tumor suppressor gene. Several mechanisms of gene inactivation have been described; in this study we have focused on p16 gene promoter methylation. In colorectal cancer p16 gene methylation is a frequent event. METHODS: 326 patients with sporadic colorectal cancer were included. DNA was extracted from tumor tissue samples obtained during the surgical procedure. Promoter methylation was analyzed using bisulfite modification and was detected by quantitative methylation-specific PCR. Frequency of p16 methylation was analyzed and compared with other clinicopathological variables. RESULTS: p16 gene methylation was detected in 24.8% of patients. Methylation was associated with differentiation grade and with tumor location: methylation was frequent in poorly differentiated tumors and had low frequency in distal colon. The p16 promoter methylation discriminated a subgroup of patients with better prognosis in poorly differentiated tumors. CONCLUSIONS: p16 methylation was a frequent event in our population and was able to induce differences in the overall survival of patients with poorly differentiated tumors.

Influence of occult hepatitis B virus infection in chronic hepatitis C outcomes.

Persistence of hepatitis B virus-DNA in the sera, peripheral blood mononuclear cells or in the liver of hepatitis B surface antigen (HBsAg)-negative patients with or without serological markers of previous exposure (antibodies to HBsAg and/or to HB-core antigen) defines the entity called occult hepatitis B infection (OBI). Co-infection with hepatitis B and hepatitis C viruses is frequent in highly endemic areas. While this co-infection increases the risk of liver disease progression, development of cirrhosis and hepatocellular carcinoma and also increases the rate of therapeutic failure to interferon-based treatments than either virus alone, a potentially negative effect of OBI on clinical outcomes and of therapeutic response to current antiviral regimes of patients with chronic hepatitis C remains inconclusive.

Circulating tumor cells in metastatic breast cancer: timing of blood extraction for analysis.

PURPOSE: Circulating tumor cells (CTCs) can be detected in the peripheral blood of around 50% of patients with metastatic breast cancer. Their numbers are an independent predictor of the patient's progression-free survival (PFS) and of overall survival (OS). However, to date, none of the studies carried out with the most commonly used system of CTC determination (the CellSearch System, approved by the US Food and Drug Administration) has examined the intra-patient variation in CTC numbers, a variation that could impact on prognosis assessment. EXPERIMENTAL DESIGN: To evaluate possible circadian variations in the number of CTCs in patients with breast cancer a pilot study was conducted in which these cells were quantified 12 h apart (at 8:00 a.m. and 8:00 p.m. of the same day) in a cohort of hospitalized patients with metastatic breast cancer. RESULTS: Out of the 58 patients included in the study, 51 were evaluable. No statistically significant differences between day-time and night-time CTC numbers were observed (p=0.8427, Wilcoxon matched pair test). Only two of the patients were classified in different prognostic categories in the morning and night determinations (5 or more CTCs=poor prognosis group; <5 CTCs=good prognosis group). The prognostic classification of the remaining 49 patients was the same at 8:00 a.m. and 8:00 p.m. CONCLUSION: The number of peripheral blood CTCs in metastatic breast cancer patients is not significantly different at 8:00 a.m. from that at 8:00 p.m. and, as such, indicates a lack of circadian rhythm with respect to CTC numbers in these patients.

[Similarities and differences among patients with symptomatic atherosclerosis affecting several territories. The AIRVAG cohort (Integral Attention to Global VAscular Risk)]. / Similitudes y diferencias entre los pacientes con aterosclerosis sintomática de distintos territorios. Cohorte AIRVAG (Atención Integral al Riesgo VAscular Global).

BACKGROUND AND OBJECTIVE: Even though atherosclerosis is a systemic disease, few prospective studies have evaluated in a thorough and systematic manner the whole vascular tree in patients with clinical damage of different territories. PATIENTS AND METHOD: Prospective protocolized study of 269 consecutive patients younger than 70, attended because of symptomatic arteriosclerosis of any territory -53% coronary (CHD), 32% cerebrovascular (CVD), 15% peripheral (PVD)-. Patients underwent evaluation of risk factors and their control, systematic non-invasive study of the vascular tree (Doppler-ultrasound) and comparison between groups according to the index territory. RESULTS: Even though all risk factors were represented in the 3 groups, male sex, smoking and diabetes were more frequent in PVD and dyslipemia was more common in CHD (p < 0.05) Abdominal aortic diameter and carotid intima-media thickness were similar for all groups, while the number of carotid plaques was higher in PVD. CHD patients more often presented left ventricular hypertrophy and reduced ejection fraction. PVD patients showed a marked reduction of the ankle-brachial index as well as increased C-reactive protein and homocysteine (p < 0.05). Severe unsuspected vascular lesions were found in 13% of cases (95% confidence interval, 9.5-17.6%). Risk factor control was better for CHD, followed by CVD and PVD, but was globally poor. CONCLUSIONS: The systematic evaluation of the vascular tree detects generalized atherosclerotic lesions, in some cases severe and clinically unsuspected. New markers to identify patients at very high risk are necessary. Peripheral vascular disease identifies a group of patients of particular risk. Risk factor control is deficient, particularly among PVD patients.

Clinical evaluation of a microsphere bead-based flow cytometry assay for the simultaneous determination of anti-thyroid peroxidase and anti-thyroglobulin antibodies.

OBJECTIVES: Multiplexing technologies based on the use of microspheres as the solid phase have opened new possibilities for the analysis of autoantibodies. As an alternative to the traditional immunoassays, it is possible to use these methods in combination with flow cytometry for simultaneous measurement of anti-thyroid peroxidase (anti-TPO) and anti-thyroglobulin (anti-Tg) antibodies. DESIGN AND METHODS: We studied 127 serum samples sent to our laboratory for the quantitation of anti-TPO and anti-Tg antibodies. Clinical information was available for all of the patients studied. The samples were analyzed simultaneously for both antibodies by flow cytometry (FIDIS, BMD, France), and individually for each of the antibodies by an automated enzyme immunoassay (UniCap, Pharmacia Diagnostics, Germany). RESULTS: A significant association between the results was observed. The kappa agreement indices between the methods were 0.859 and 0.832 for anti-TPO and anti-Tg, respectively. Discrepant results between the two techniques were observed with no common cause. Anti-TPO and anti-Tg antibodies exhibited a non-Gaussian distribution. The areas under the ROC curves were similar for both methods used; for anti-TPO, 0.884 (Pharmacia) and 0.853 (BMD), and for anti-Tg, 0.833 (Pharmacia) and 0.837 (BMD). CONCLUSION: Cytometry multiplex technology offers a true alternative to conventional immunoassays in the analysis of anti-TPO and anti-Tg antibodies.