Relationship between FEV1 and arterial stiffness in elderly people with chronic obstructive pulmonary disease.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is highly prevalent in the elderly, and both COPD and age per se are associated with cardiovascular morbidity. AIMS: We tested the hypothesis that in elderly COPD patients airflow limitation is associated with arterial stiffness and the relationship, if any, is related to endothelial function and systemic inflammation. METHODS: We evaluated lung function, augmentation index (AIx), flow-mediated dilation (FMD), Interleukin-6 (IL-6), and asymmetric dymethilarginine (ADMA) levels in 76 subjects (mean age 73.9 years, SD 6.2) attending a geriatric outpatient clinic. RESULTS: Participants with COPD (N = 41) and controls (N = 35) did not differ in terms of AIx (30 vs 28.2 %, P = 0.30) and FMD (14.2 vs 12.3 %, P = 0.10). Similarly, the two groups did not differ with respect to mean concentrations of inflammation markers (IL-6 and C-reactive protein) and ADMA. Among COPD participants there was an inverse correlation between AIx and Forced Expiratory Volume in the first second (r = -0.349, P = 0.02). This relationship remained significant after correction for potential confounders, including markers of inflammation and ADMA levels (ß = -0.194, P = 0.001). DISCUSSION: According to the results of this study, among COPD patients, bronchial patency and AIx are inversely related, and the relationship is explained neither by endothelial function nor by systemic inflammation. CONCLUSIONS: In elderly COPD people, increased arterial stiffness is related to reduced pulmonary function and it seems worth testing as a potential marker of higher cardiovascular risk.

Procalcitonin and mid-regional pro-adrenomedullin test combination in sepsis diagnosis.

BACKGROUND: The early diagnosis of sepsis plays a central role in patient management. Many mediators to be the cause of sepsis have been proposed. In the present study the combined measurement of procalcitonin (PCT) and mid-regional pro-adrenomedullin (MR-proADM) and their appropriate cut-off values in sepsis patients were evaluated. METHODS: PCT and MR-proADM were measured with commercially available immunoluminometric assays (Brahms, Hennigsdorf, Germany) in 200 septic patients, 90 patients with SIRS and 30 healthy individuals. Data were analyzed with ROC curve analysis and likelihood ratios with the MedCalc 11.6.1.0 package. RESULTS: Healthy controls and non-infectious SIRS were clearly distinguished from sepsis patients using the follow ing cut-off values: 0.30 ng/mL for PCT and 1 nmol/L for ADM. In the 200 septic patients the areas under the curve (AUCs) for PCT and MR-proADM were 0.921 and 0.977, respectively, with a statistically significant difference between the two areas of 0.0563 (p = 0.0002). Gram-positive, Gram-negative, yeast and polymicrobial sepsis patients showed different geometric means of the two biomarkers: this difference was relevant in Gram-positive sepsis and in yeast sepsis, 0.0819 (p = 0.0076) and 0.188 (p = 0.0062), respectively. The combined use of PCT and MR-proADM gave a post-test probability of 0.998 in the cohort of all septic patients. By test combination the post-test probability changed from 0.803 to 0.957 in Gram-positive sepsis and from 0.928 to 0.995 in yeast sepsis. CONCLUSIONS: In conclusion, data from this study demonstrates that the combined use of PCT and MR-proADM, may substantially improve the early diagnosis of sepsis.

Early magnesium reduction in advanced colorectal cancer patients treated with cetuximab plus irinotecan as predictive factor of efficacy and outcome.

INTRODUCTION: Magnesium plays a role in a large number of cellular metabolic reactions. Cetuximab is able to induce hypomagnesemia by interfering with magnesium (Mg(2+)) transport in the kidney. We designed this trial to investigate if Mg(2+) serum level modifications may be related with clinical response and outcome in advanced colorectal cancer patients during treatment with cetuximab plus irinotecan. EXPERIMENTAL DESIGN: Sixty-eight heavily pretreated metastatic colorectal cancer patients were evaluated for Mg(2+) serum levels at the following time points: before; 6 hours; and 1, 7, 14, 21, 50, and 92 days after the start of treatment. RESULTS: Basal Mg(2+) median levels were significantly decreased just 7 days after the first anticancer infusion and progressively decreased from the 7th day onward, reaching the highest significance at the last time point (P < 0.0001). Twenty-five patients showed a reduction in median Mg(2+) circulating levels of at least 20% within the 3rd week after the first infusion. Patients with this reduction showed a response rate of 64.0% versus 25.6% in the nonreduced Mg(2+) group. The median time to progression was 6.0 versus 3.6 months in the reduced Mg(2+) group and in that without reduction, respectively (P < 0.0001). Overall survival was longer in patients with Mg(2+) reduction than in those without (10.7 versus 8.9 months). CONCLUSIONS: Our results confirm that cetuximab treatment may induce a reduction of Mg(2+) circulating levels and offer the first evidence that Mg(2+) reduction may represent a new predictive factor of efficacy in advanced colorectal cancer patients treated with cetuximab plus irinotecan.

Repeated intermittent low-dose therapy with zoledronic acid induces an early, sustained, and long-lasting decrease of peripheral vascular endothelial growth factor levels in cancer patients.

PURPOSE: On the basis of stimulating data on animals reporting that weekly regimens of zoledronic acid (ZA) were effective in reducing skeletal tumor burden, we designed a study on humans to investigate the potential antiangiogenic role of a weekly low-dose therapy with ZA in patients with malignancies. EXPERIMENTAL DESIGN: Twenty-six consecutive patients with advanced solid cancer and bone metastases received 1 mg of ZA every week for four times (days 1, 7, 14, and 21) followed by 4 mg of ZA with a standard 28-day schedule repeated thrice (days 28, 56, and 84). Patients were prospectively evaluated for circulating levels of vascular endothelial growth factor (VEGF) just before the beginning of drug infusion (0) and again at 7, 14, 21, 28, 56, and 84 days after the first ZA infusion. RESULTS: The median VEGF basal value showed an early statistically significant (P = 0.038) decrease 7 days after the first 1-mg infusion of ZA. This effect on VEGF-circulating levels persisted also after the following 1-mg infusions at 14 (P = 0.002), 21 (P = 0.001), and 28 days (P = 0.008). Interestingly, the decrease of VEGF-circulating levels persisted also at each programmed time point during the second phase of the study (ZA 4 mg every 4 weeks). No significant differences were recorded in platelet levels, WBC count, or hemoglobin concentration before and after each ZA infusion. CONCLUSIONS: In the present study, we report that a repeated low-dose therapy with ZA is able to induce an early significant and long-lasting decrease of VEGF levels in cancer patients.

Circulating VEGF reduction, response and outcome in advanced colorectal cancer patients treated with cetuximab plus irinotecan.

OBJECTIVE: We designed this trial to investigate if modifications in levels of circulating vascular endothelial growth factor (VEGF) may be related to clinical response and outcome in advanced colorectal cancer patients during treatment with a weekly combination of cetuximab plus irinotecan. METHODS: A total of 45 heavily pretreated metastatic colorectal cancer patients were prospectively evaluated for circulating levels of VEGF during the treatment with cetuximab plus weekly irinotecan. VEGF circulating levels were assessed at the following time points: just before and at 1, 21, 50 and 92 days after the start of cetuximab plus irinotecan treatment. RESULTS: Basal VEGF median levels were significantly decreased just 1 day after the first anticancer infusion (p = 0.016) and reached the highest statistical significance 92 days after the first infusion (p < 0.0001). A total of 22 patients showed a reduction in median VEGF circulating levels of at least 50% 92 days after the first infusion with respect to the basal time point. For patients with at least a 50% reduction in VEGF levels, the response rate was 45.5% compared with 8.7% in the nonreduced VEGF group (p = 0.014). The median time to progression was 6 months in the reduced VEGF group versus 3.9 months in the other patients (p < 0.0001). In addition, overall survival was longer in patients with VEGF reduction (11.0 months) than in patients without (9.6 months; p = 0.01). CONCLUSION: These data represent the first evidence that suggests a role of VEGF reduction in the prediction of efficacy of treatment with cetuximab plus weekly irinotecan in heavily pretreated advanced colorectal cancer patients.

Zoledronic acid-related angiogenesis modifications and survival in advanced breast cancer patients.

The proven antiangiogenic activity of zoledronic acid, a third-generation bisphosphonate widely used in bone metastatic cancer patients, led us to investigate if the vascular endothelial growth factor (VEGF)-related zoledronic acid modifications are correlated with survival advantages in advanced breast cancer patients. Forty-two consecutive breast cancer patients with scintigraphic and radiographic evidence of bone metastases were treated with a single infusion of 4 mg zoledronic acid before anticancer chemotherapy. The patients were prospectively evaluated for circulating levels of VEGF and interferon-gamma (IFN-gamma) just before and at 1, 2, 7, and 21 days after zoledronic acid infusion. Afterward, clinical outcome was prospectively monitored. The basal serum VEGF median levels were significantly decreased at each time point, but the major reduction was recorded 21 days after the infusion. In particular, 25 patients of 42 (59.5%) experienced a reduction of at least 25% in the VEGF circulating levels. In contrast, no statistically significant modifications of the IFN-gamma serum levels were recorded. We stratified patients on the basis of this VEGF reduction 21 days after the infusion. No differences in patient features were recorded between those with or without the VEGF reduction. The analysis of survival showed that patients with a reduction in the VEGF circulating levels had a longer time to first skeletal-related event (p = 0.0002), time to bone progression disease (p = 0.0024), and time to performance status worsening (p = 0.0352) than those without the VEGF reduction. No statistically significant differences were recorded in terms of overall survival and time to visceral progression. This study confirms that zoledronic acid could have an in vivo antiangiogenic property and that the VEGF modifications may represent a surrogate marker able to predict time to first skeletal-related event, time to bone progression disease, and time to worsening of performance status.

Fever after zoledronic acid administration is due to increase in TNF-alpha and IL-6.

The most common adverse event typically associated with bisphosphonate therapy is transient fever. The aim of this study was to define the role of the main cytokines of the acute-phase reaction interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) involved in the pathogenesis of zoledronic acid-induced fever. Eighteen consecutive cancer patients with bone metastases were treated, for the first time, with a single dose of 4 mg zoledronic acid infusion. They were prospectively evaluated for circulating TNF-alpha, interferon-gamma (IFN-gamma), and IL-6 levels at different times, just before and 1, 2, 7, and 21 days after diphosphonate infusion. Clinical and standard laboratory parameters were recorded at the same time points. TNF-alpha circulating levels increased significantly 1 and 2 days after zoledronic acid infusion (respectively, p = 0.002 and p < 0.001) and then decreased to levels similar to the basal levels. IL-6 levels increased significantly 1 day after the infusion (p = 0.007), returning to values similar to the median basal values 2 days after zoledronic acid administration. Moreover, in patients who experienced fever, the TNF-alpha and IL-6 increases were higher than in patients without fever. No statistically significant differences in IFN-gamma were identified at different time points in patients with and without fever. Our results show that zoledronic acid induces transient TNF-alpha and IL-6 increases and that these increases are higher in patients who have developed fever, suggesting that these cytokines could be responsible for fever pathogenesis. The sharp reduction in serum calcium levels observed in patients with fever may be related to zoledronic acid pharmacokinetic modifications.

Zoledronic acid induces significant and long-lasting modifications of circulating angiogenic factors in cancer patients.

PURPOSE: The commercial availability of zoledronic acid, a third generation bisphosphonate, prompted us to evaluate the modifications in angiogenic cytokines levels after a single i.v. infusion of this drug. EXPERIMENTAL DESIGN: Thirty consecutive cancer patients with scintigraphic and radiographic evidence of bone metastases were treated with a single infusion of 4 mg of zoledronic acid before any chemotherapy. The patients were prospectively evaluated for circulating levels of vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) just before and at 1, 2, 7, and 21 days after zoledronic acid infusion. RESULTS: Basal serum VEGF median levels were significantly decreased at days 2 (-23%), 7 (-28%), and 21 (-34%) after zoledronic acid infusion (P = 0.0498, 0.0090, and 0.0011, respectively). Serum PDGF levels were significantly decreased by 25% 1 day after zoledronic acid infusion (P = 0.0032). This effect on circulating PDGF levels persisted for 2 days after bisphosphonate infusion (P = 0.0050). PDGF levels had returned to values similar to the median basal value at 7 and 21 days. Moreover, a linear regression model with variance analysis showed a significant positive correlation between basal VEGF and PDGF values but not at the following time points. No significant differences were recorded in platelet levels, WBC count, or hemoglobin concentration before and after zoledronic acid single infusion. CONCLUSIONS: This study confirms that zoledronic acid could have an in vivo antiangiogenic property through a significant and long-lasting reduction in serum VEGF levels.

Erythromycin-resistant pharyngeal isolates of Streptococcus pyogenes recovered in Italy.

Three classes of macrolide resistance phenotypes and three different erythromycin resistance determinants were found among 127 erythromycin-resistant group A streptococcal (GAS) isolates recovered from 355 (35.8%) pediatric pharyngitis patients in Rome, Italy. According to emm and sof sequence typing results, erythromycin-resistant isolates comprised 11 different clonal types. Remarkably, 126 of the 127 macrolide-resistant isolates were serum opacity factor (sof) gene positive. These data suggest a strong association between macrolide resistance and the presence of sof among GAS isolates recovered from Italian pediatric pharyngitis patients.

Pamidronate induces modifications of circulating angiogenetic factors in cancer patients.

PURPOSE: Recently, new experimental data suggested that, besides inhibiting osteoclasts, bisphosphonate may also have an antitumor effect. Antiangionetetic activity is one of the possible mechanisms of anticancer activity attributed to bisphosphonates. The purpose of this study was to evaluate the modifications in angiogenic cytokines levels after pamidronate infusion. EXPERIMENTAL DESIGN: Twenty-five consecutive cancer patients with bone metastases treated monthly with disodium pamidronate infusion were evaluated prospectively for circulating levels of vascular endothelial growth factor (VEGF), gamma-IFN, interleukin (IL)-6, and IL-8 at different time points: just before and after 1, 2, and 7 days after pamidronate infusion. RESULTS: Basal VEGF levels decreased significantly 1, 2, and 7 days after pamidronate infusion. gamma-IFN and IL-6 levels increased 1 day after the infusion but rapidly decreased after 2 days. Moreover, our data showed a statistically significant negative correlation between VEGF and gamma-IFN levels (P < 0.0001) and a positive correlation between VEGF and IL-8 (P = 0.04). CONCLUSIONS: This study confirms that pamidronate could have antiangiogenic properties through a significant and lasting decrease of VEGF serum levels.