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Background: Bevacizumab and erlotinib have been demonstrated to prolong overall survival in patients with non-squamous non-small cell lung cancer (NSCLC). We designed a four-arm Phase III trial to evaluate the efficacy and toxicity of the combination of docetaxel, carboplatin, bevacizumab, and erlotinib in the first-line treatment of patients with NSCLC. Methods: A total of 229 patients with stage IIIb/IV non-squamous NSCLC were treated with two cycles of carboplatin (area under the concentration-time curve 5.5) and docetaxel 100 mg/m² as chemotherapy. After completion of two treatment cycles, patients were evaluated for response and divided into four groups: 61/229 continued with four more cycles of chemotherapy (control group), 52/229 received chemotherapy plus erlotinib 150 mg daily, 56/229 received chemotherapy plus bevacizumab 7.5 mg/kg, and 60/229 were treated with the combination of chemotherapy, erlotinib, and bevacizumab until disease progression. The primary endpoint was overall survival. Results: Over 4 years of follow-up, there was no statistically significant difference in survival and time to progression between the four treatment groups. After two cycles of chemotherapy, responders and nonresponders were divided according to their response in order to examine the role of initial response as an independent factor in survival and response when a biological agent is combined with chemotherapy. Nonresponders, who received additional therapy with bevacizumab or combination therapy, had a survival benefit [657 days (95% confidence interval 349-970) and 681 days (95% conidence interval 315-912), respectively], which was statistically significant compared with continuation of cytotoxic chemotherapy (P , 0.001). The combination therapy had a safety profile comparable with that of bevacizumab and erlotinib taken individually. Conclusion: Administration of bevacizumab and erlotinib in combination with first-line chemo- therapy, followed by bevacizumab and erlotinib monotherapy as maintenance, showed promising results in patients with NSCLC, with reduced toxicity as compared with chemotherapy alone, but did not translate into longer overall survival. [ABSTRACT FROM AUTHOR]

Hemodialysis (HD) patients are characterized by impaired T-cell function at least in part because of T-cell zeta-chain downregulation due to inflammation. Angiogenin responds as an acute phase reactant, is increased in HD patients, suppresses T-cell function and increased angiogenin level is co-localized with T-cell zeta-chain downregulation in various pathologies. Angiogenin can inhibit translation of proteins, which lack internal ribosomal entry sites in the corresponding mRNAs. In this study, the possible effect of angiogenin on T-cell zeta-chain downregulation was evaluated. Thirty HD patients and 21 healthy volunteers participated. T-cell zeta-chain expression was assessed with flow cytometry, plasma angiogenin and serum IL-6 with ELISA and serum C-reactive protein with an immunoturbidimetric method. Two available software tools were used for predicting the presence or not of internal ribosomal entry sites in T-cell zeta-chain mRNA sequence. In silico analysis of T-cell zeta-chain mRNA sequence failed to reveal the presence of internal ribosomal entry sites. T-cell zeta-chain expression was lower in HD patients than in healthy volunteers (1.86 ± 0.63 vs. 4.73 ± 3.22). In HD patients, C-reactive protein as well as IL-6 were higher than in healthy volunteers (10.04 ± 15.13 mg/L vs. 3.43 ± 0.98 mg/L and 15.06 ± 13.08pg/mL vs. 2.11 ± 2.10 pg/mL respectively). Angiogenin was higher in HD patients than in healthy volunteers (483.20 ± 154.07 ng/mL vs. 259.98 ± 64.15 ng/mL). Neither C-reactive protein, nor IL-6 was associated with angiogenin or T-cell zeta-chain expression. Angiogenin concentration was negatively related to the expression of T-cell zeta-chain (r = −0.410, P = 0.025). Increased angiogenin may contribute to decreased T-cell zeta-chain expression in HD patients. [ABSTRACT FROM AUTHOR]

Introduction: Coronary heart disease (CHD) is the leading cause of death in hemodialysis (HD) patients. Inflammation contributes to the pathogenesis of atherosclerosis in this population. Indoleamine 2,3-dioxygenase (IDO), an enzyme with immunomodulatory properties, was evaluated in HD patients with or without CHD. Methods: Of the total of 66 HD patients, 22 of them with CHD were confirmed by coronary angiography and 24 healthy volunteers were enrolled in the study. Plasma IDO was assessed by means of enzyme-linked immunosorbent assay. Serum interleukin-6 (IL-6) and C-reactive protein (CRP) were also measured. Results: Compared with healthy volunteers, plasma IDO concentration was markedly increased in HD patients (median 8.04 ng/mL vs. 48.9 ng/mL). Serum IL-6 and CRP were also significantly increased in HD patients. Compared with HD patients without CHD, plasma IDO concentration was significantly increased in HD patients with CHD (median 38.6 ng/mL vs. 74.5 ng/mL). Neither IL-6 nor CRP differed between the last two groups. IDO was negatively correlated with IL-6 and CRP. Conclusion: IDO concentration is increased in HD patients and is increased further in HD patients with CHD. It remains to be elucidated if increased IDO plays a direct role in the pathogenesis of atherosclerosis or if it affects atherosclerosis indirectly by curtailing chronic inflammation or both. [ABSTRACT FROM AUTHOR]

Introduction. Serotonin receptors are present in osteoblasts and osteoclasts, and serotonin affects bone metabolism. The association of plasma serotonin with markers of bone formation and bone resorption in hemodialysis patients was evaluated. Materials and Methods. Twenty-four hemodialysis patients (11 diabetics) and 22 healthy volunteers were enrolled into the study. Serotonin was assessed in platelet-free plasma, whereas the markers of osteoblastic activity N-terminal midfragment osteocalcin and total procollagen type-1 aminoterminal propeptide as well as the marker of osteoclastic activity β-isomerized C-terminal cross-linked peptide of collagen type I were measured in serum. Serum intact parathyroid hormone was also assessed. Results. Serotonin did not significantly differ between hemodialysis patients and healthy volunteers. All evaluated markers of bone metabolism and intact parathyroid hormone were much higher in hemodialysis patients. Serotonin was significantly correlated with all evaluated markers of bone metabolism in hemodialysis patients. Serotonin was reversely related to the patients' age. Serotonin, osteocalcin, procollagen type-1 aminoterminal propeptide, and β-isomerized C-terminal cross-linked peptide of collagen type I were much lower in diabetic hemodialysis patients. Conclusions. Serotonin may increase both bone formation and bone resorption in hemodialysis patients. The reverse relation of serotonin to patients' age as well as its lower levels in diabetic hemodialysis patients indicate that low plasma serotonin may contribute to the higher incidence of low-turnover bone disease that characterizes old and 'diabetic hemodialysis patients. [ABSTRACT FROM AUTHOR]

Introduction. Angiogenesis plays a role in the pathogenesis of coronary heart disease (CHD) and diabetes mellitus (DM) pathology, and certain angiogenic factors are increased by inflammation. The aim of this study was to evaluate plasma angiogenin and vascular endothelial factor A (VEGFA) levels in hemodialysis patients, as well as the effect of CHD, DM, and inflammation on these markers. Materials and Methods. Sixty-six hemodialysis patients were enrolled in the study, of whom 22 (33.3%) suffered from CHD, 22 (33.3%) from DM, and 28 (42.4%) from inflammation. They were compared with 24 healthy volunteers. Plasma angiogenin and VEGFA were assessed by means of enzyme-linked immunosorbent assay, and serum C-reactive protein was measured with an immunoturbidimetric method. These markers were compared between hemodialysis patients with and without CHD, DM, and inflammation. Results. Compared to healthy volunteers, plasma angiogenin was significantly higher in hemodialysis patients (263.57 ± 65.95 ng/mL versus 499.15 ± 175.68 ng/mL; P < .001). Similarly, plasma VEGFA was markedly increased in hemodialysis patients (median, 60.50 pg/ mL; range, 280 pg/mL), compared to healthy volunteers (median, 28.84 pg/mL; range, 59.40 pg/mL; P < .001). Neither angiogenin nor VEGFA levels differed significantly between hemodialysis patients with and without CHD, DM, or inflammation. Conclusions. Plasma angiogenin and VEGFA levels are markedly increased in hemodialysis patients, but not associated with CHD, DM, or inflammation among hemodialysis patients. [ABSTRACT FROM AUTHOR]

Introduction. In hemodialysis patients, 25-hydroxyvitamin D conversion to active 1,25-dihydroxyvitamin D by the kidneys is very limited. The expression of both vitamin D receptor and 1α-hydroxylase in cells of the immune system and in both osteoblasts and osteoclasts makes it possible that 25-hydroxyvitamin D could play an important role in both inflammation and bone metabolism acting in a autocrine and/or paracrine way in these patients. Materials and Methods. Thirty-three hemodialysis patients not under vitamin D receptor agonist treatment were enrolled into the study. Serum levels of 25-hydroxyvitamin D, C-reactive protein (CRP), interleukin-6 (IL-6), receptor activator of nuclear factor-κB ligand (RANKL), and osteoprotegerin, as well as intact parathyroid hormone (PTH) were assessed by immunoassays. Results. Regarding inflammation, 25-hydroxyvitamin D inversely correlated with both CRP and IL-6. Regarding bone metabolism, 25-hydroxyvitamin D was positively related to osteoprotegerin, but negatively to the RANKL. The latter could be the result of PTH suppression by 25-hydroxyvitamin D, since 25-hydroxyvitamin D negatively correlated with PTH, which in turn was positively related to RANKL. Conclusions. Serum 25-hydroxyvitamin D is inversely correlated with markers of inflammation and may suppress osteoclastic activity in hemodialysis patients. [ABSTRACT FROM AUTHOR]

Testicular cancer is a disease with elusive pathogenesis. Recent studies demonstrated a relationship between insulin- like growth factor (IGF) signaling pathway and the pathogenesis of various types of cancer. On the other hand inconclusive data correlate increasing height, a trait depending on IGF signaling pathway, with increasing incidence of testicular cancer. Thus, it is possible that IGF system may be implicated in the pathogenesis of germ cell tumors. The purpose of the study was to identify the role of IGF signaling pathway in the pathogenesis of testicular germ cell tumors (GCTs). 50 patients with GCTs prior to the onset of chemotherapy and 16 male age matched controls were enrolled. Three blood samples were drawn from the patients, the first at baseline, the second 20-30 days after completion of the second cycle of chemotherapy and the third 9-14 months after the completion of chemotherapy; and one blood sample was drawn from the controls. We measured serum IGF-1 and IGFBP-3 and calculated their molar ratio using quantitative sandwich enzyme immunoassay technique. Patients and controls had similar demographic characteristics. Mean IGF-1/IGFBP-3 molar ratio was higher in patients than controls (0.27±0.07 vs. 0.11±0.03; p=0.02'7). IGF-1 decreased significantly between the baseline and 1 year after chemotherapy was completed (261.2±483 vs. 96.4±23.1 ng/mL, respectively; p<0.001) and between the second sample and the third sample (205.7±41.7 vs. 96.4±23.1 ng/mL; p<0.001 IGFBP-3 was increased after chemotherapy (mean values of first and second samples were 3545±687.3 vs. 4714±827.1 ng/mL; p=0.045, and mean values between first and third samples were 3591±697.6 vs. 5145±1073.2 ng/mL; p=0.005 IGF1/IGFBP3 molar ratio was found to decrease after initiation and completion of chemotherapy (mean values were: 0.269±0.05 vs. 0.211±0.04; between the first and third samples, p=0.035; 0.308±0.07 vs. 0.083±0.02 between the second and third samples, p<0.001and 0.211±0.04 vs. 0.084±0.02 between the first and second samples, p<0.00). The concept that IGF signaling system has a role in germ cell cancer pathogenesis is an appealing idea and our study seems to provide further evidence in favor of our initial hypothesis, although larger prospective studies are needed to further elucidate it. [ABSTRACT FROM AUTHOR]