Fabrizio Battistoni

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.

Fever After Zoledronic Acid Administration Is Due to Increase in TNF-α 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-α (TNF-α) 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-α, interferon-γ (IFN-γ), 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-α 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 ...

Routine molecular identification of enterococci by gene-specific PCR and 16S ribosomal DNA sequencing.

ABSTRACT For 279 clinically isolated specimens identified by commercial kits as enterococci, genotypic identification was performed by two multiplex PCRs, one with ddlE. faecalis andddlE. faecium primers and another withvanC-1 and vanC-2/3 primers, and by 16S ribosomal DNA (rDNA) sequencing. For 253 strains, phenotypic and genotypic results were the same. Multiplex PCR allowed for the identification of 13 discordant results. Six strains were not enterococci and were identified by 16S rDNA sequencing. For 5 discordant and 10 concordant enterococcal strains, 16S rDNA sequencing was needed. Because many supplementary tests are frequently necessary for phenotypic identification, the molecular approach is a good alternative.

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 (Mg2+) transport in the kidney. We designed this trial to investigate if Mg2+ 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 Mg2+ 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 Mg2+ 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 Mg2+ 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 Mg2+ group. The median time to progression was 6.0 versus 3.6 months in the reduced Mg2+ group and in that without reduction, respectively (P < 0.0001). Overall survival was longer in patients with Mg2+ reduction than in those without (10.7 versus 8.9 months). Conclusions: Our results confirm that cetuximab treatment may induce a reduction of Mg2+ circulating levels and offer the first evidence that Mg2+ reduction may represent a new predictive factor of efficacy in advanced colorectal cancer patients treated with cetuximab plus irinotecan.

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.

Erythromycin-Resistant Pharyngeal Isolates of Streptococcus pyogenes Recovered in Italy

ABSTRACT 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.

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

Abstract 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 following 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.

Diagnostic Value of Cytokine Assays in Cerebrospinal Fluid in Culture-Negative, Polymerase Chain Reaction-Positive Bacterial Meningitis

Abstract Analysis of bacterial DNA using a polymerase chain reaction performed with broad-range eubacterial 16S rDNA primers may yield a diagnosis of bacterial meningitis in cases where Gram staining of cerebrospinal fluid (CFS), antigen detection techniques or culture fail. Since this PCR technique occasionally gives false-positive results due to contamination of samples or laboratory reagents, a study was performed to establish the diagnostic value of assaying concentrations of tumour necrosis factor-α (TNF-α) and interleukin-10 (IL-10) in 90 CSF samples. A high correlation was found between a positive PCR result and the concentrations of TNF-α and IL-10, indicating that cytokine assays may be used as a confirmatory test. The findings suggested that a combination of the PCR technique, amplicon sequencing and assay of TNF-α and IL-10 concentrations in CSF is a reliable and cost-effective procedure for diagnosis of culture-negative bacterial meningitis.

Pamidronate (P) 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.