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.     

Congenital mono-ophthalmia syndrome

Three patients affected by the congenital mono-ophthalmia syndrome were submitted to horizontal eye movements recording. The aim was to study the nystagmus and its characteristics, in order to give information that could explain signs and symptoms of the syndrome. Eye movements recording and analysis displayed a jerk nystagmus with a decreasing-velocity exponential slow phase, characteristic of a latent/manifest-latent nystagmus. The intensity of nystagmus decreased in adduction of the viewing eye, and increased in abduction in accordance with Alexander's law. The fast phase was toward the viewing eye. There was no reversal of the fast phase, nor an instability of gaze in the blind eye.     

Pregnancies in an 18-Year Follow-up after Biliopancreatic Diversion

Background: 239 pregnancies occurred in 1136 women who had undergone biliopancreatic diversion (BPD). Methods: There were 73 abortions, and 14 pregnancies are presently in their course. The 152 term pregnancies (six twins) occurred in 129 women 2-173 months (mean 42.7) after BPD. Mean age and current excess weight were 31.4 years (20-42) and 29.1% (-6.9-78.2), and mean excess weight loss was 72.9% (30.4-110.5). Results: Mean weight gain during pregnancy was 6.2 kg (-21-25). In 32 patients (21%), parenteral nutritional support was needed. In all the other patients (79%), the usual supplementations were given. Of the newborns, 122 were delivered at term (84.7%) with a mean weight of 2842.4 g (1760-4600 g) and a mean length of 48.5 cm (43-59 cm), while the 22 preterm babies (15.3%) weighed 2151.1 g (1400-3850 g) and had a length of 44.6 cm (33-56 cm). Forty infants (27.8%) were small for gestational age but 17 of them weighed more than 2500 g. Eleven twins (one abortion at 26th week) were also delivered, with a mean weight of 2088.6 g (1200-3100 g) and a mean length of 45.6 cm (35-50 cm). Delivery was spontaneous in 85 instances (56%), while vacuum extractor was used in one, and 66 cesarean sections were performed. There were two birth malformations, one infant died after surgery for meconium obstruction and two died from unknown causes. Of the 129 women, 35 had been infertile before BPD. Conclusions: Disappearance of infertility and decrease of pregnancy risk are to be considered among the beneficial effects of weight reduction following BPD.     

p53 Accumulation Is a Prognostic Factor in Intestinal-Type Gastric Carcinoma but Not in the Diffuse Type

Background: The prognostic value of p53 nuclear accumulation in gastric cancer is still unclear, as shown by the discordant results still reported in the literature. In this study, we evaluated the correlation between p53 accumulation and long-term survival of patients resected for intestinal and diffuse-type gastric cancer.Methods: Eighty-three patients with carcinoma of the intestinal type and 53 patients with carcinoma of the diffuse type were included in the study. Immunohistochemical staining of the paraffin sections was performed by using monoclonal antibody DO1; cases were considered positive when nuclear immunostaining was observed in 10% or more of the tumor cells. Prognostic significance of different variables was investigated by univariate and multivariate analysis.Results: p53 positivity was found in 51.8% of intestinal-type and 50.9% of diffuse-type cases. No significant correlation between the rate of p53 overexpression and age, sex, tumor location, tumor size, depth of invasion, lymph node involvement, distant metastases, and surgical radicality was found in the two groups of patients. A statistically significant difference in survival rate was observed between p53-negative and p53-positive cases in the intestinal type (P < .05), confirmed by multivariate analysis (P < .005; relative risk = 3.09). On the contrary, no correlation with survival was found in diffuse-type cases according to p53 overexpression.Conclusions: These results suggest that the immunohistochemical detection of p53 accumulation is a useful indicator of poor prognosis in the intestinal but not in the diffuse type of gastric cancer, and are indicative of distinct molecular pathways and pattern of progression in the two histotypes.     

Hemodynamic performance of small-size bileaflet valves: pressure drop and laser Doppler anemometry study comparison of three prostheses

Laser Doppler anemometry (LDA) is a single-point technique which is unparalleled to detect accurately the local properties of the velocity field in a turbulent flow, such as that generated by a prosthetic heart valve (PHV). We propose a correlation between the structure of the flow field in three 19 mm bileaflet PHVs (Sorin Bicarbon, St. Jude Standard, St. Jude HP), investigated at peak systole (6 L/min cardiac output [CO]) with LDA, in kinematic and geometric similarity, and the global parameter of transvalvular pressure drop measured in both steady and pulsatile conditions. The pressure transducers of the same apparatus were used to characterize pressure drops at different flow rates whereas the steady-flow case was studied with a highly accurate tester built in our laboratory. The 2 St. Jude models rank according to their internal orifice diameter (ID) with the standard model (with a smaller ID) providing higher pressure drops for each flow rate. Sorin Bicarbon, due to its leaflet geometry, generates a more complex flow field with respect to the 2 St. Jude flat-leaflet models and shows improved hemodynamical behavior in pulsatile conditions with respect to the stationary case due to differences in pressure recovery. This study can provide insights into a PHV's local flow structure and global hemodynamical parameters.     

Alpha1 acid glycoprotein binds to imatinib (STI571) and substantially alters its pharmacokinetics in chronic myeloid leukemia patients.

PURPOSE: Imatinib (Glivec) is a potent inhibitor of bcr/abl, an oncogenic fusion protein that causes chronic myelogenous leukemia (CML). alpha1 acid glycoprotein (AGP) binds to imatinib with high affinity and inhibits imatinib activity in vitro and in vivo in an animal model. A pharmacokinetics analysis of imatinib was undertaken in CML patients. EXPERIMENTAL DESIGN: Imatinib plasma concentrations were measured in 19 CML patients treated with imatinib (400 or 600 mg/day). Five patients received a concomitant short-term course of clindamycin (CLI). RESULTS: A positive correlation between AGP and imatinib plasma levels was observed. CLI administration decreased imatinib plasma concentrations, evaluated as area under the curve (AUC) and peak concentrations (C(max)). The effects of a bolus of CLI was studied in three patients on imatinib 23 h after the last imatinib dose. Within 5-10 min in three of three cases, CLI caused a decrease in imatinib plasma concentrations of 2.6-, 2.7-, and 4.7-fold, respectively. In vitro experiments using fresh blasts from CML patients showed that AGP, at concentrations observed in the patients, decreased imatinib intracellular concentrations up to 10 times and blocked imatinib activity. The incubation with CLI restored imatinib intracellular concentrations and biological activity. CONCLUSION: AGP exerts significant effects of the pharmacokinetics, plasma concentrations, and intracellular distribution of imatinib in CML patients; these data indicate that plasma imatinib levels represent unreliable indicators of the cellular concentrations of this molecule.     

Delivery room strategies and outcomes in preterm infants with gestational age 24-28 weeks.

OBJECTIVE: To investigate the effect of different delivery room strategies on survival, short term morbidity, and outcomes in extremely premature infants. METHODS: This retrospective cohort study included all preterm infants with a gestational age between 24 and 28 weeks who were born in 1992-1997 (period A; n = 161) and in 1998-2003 (period B; n = 163). In period A, elective intubation was performed. In period B, if spontaneous breathing was present, nasal continuous positive airway pressure (nCPAP) was applied. RESULTS: Survival rate and the number of never-intubated infants significantly increased in period B. No differences were found concerning short-term morbidity. Among major outcomes, the need for retinopathy of prematurity (ROP) surgery and the length of stay were significantly lower in period B. Subgroup analysis showed no significant differences from period A to period B in infants with gestational age 24-26 weeks. In the 27-28 weeks subgroup, the never-intubated infants rate increased from 2.8% to 21.3% and survival rate increased from 63% to 79%. A reduced need for ROP surgery and a shorter hospital stay were also observed. CONCLUSIONS: Changes in delivery room strategy tending to reduce mechanical ventilation in extremely premature infants are likely to benefit essentially infants of 27-28 weeks of gestation. Extension of such benefits to premature infants at the limit of viability requires further research.     

ABL mutations in late chronic phase chronic myeloid leukemia patients with up-front cytogenetic resistance to imatinib are associated with a greater likelihood of progression to blast crisis and shorter survival: a study by the GIMEMA Working Party on Chronic Myeloid Leukemia.

PURPOSE: Point mutations within the ABL kinase domain of the BCR-ABL gene have been associated with clinical resistance to imatinib mesylate in chronic myeloid leukemia (CML) patients. To shed further light on the frequency, distribution, and prognostic significance of ABL mutations, we retrospectively analyzed a homogeneous cohort of late chronic phase CML patients who showed primary cytogenetic resistance to imatinib. PATIENTS AND METHODS: Using denaturing high-performance liquid chromatography (D-HPLC) and sequencing, we screened for ABL mutations in a total of 178 bone marrow and/or peripheral blood samples from 40 late chronic phase CML patients homogeneously treated with imatinib 400 mg/d, who did not reach a major cytogenetic response at 12 months. RESULTS: Mutations were found in 19 of 40 patients (48%). Mutations were already detectable by D-HPLC at a median of 3 months from the onset of therapy. The presence of a missense mutation was significantly associated with a greater likelihood of subsequent progression to accelerated phase/blast crisis (P = .0002) and shorter survival (P = .001). Patients carrying mutations falling within the P-loop seemed to have a particularly poor outcome in terms of time to progression (P = .032) and survival (P = .045). CONCLUSION: Our results show that, irrespective of the hematologic response, monitoring for emerging mutations in the first months of therapy may play a role in detecting patients with worse prognosis, for whom a revision of the therapeutic strategy should be considered.     

Oleoylethanolamide inhibits food intake in free-feeding rats after oral administration.

Oleoylethanolamide (OEA) is an endogenous lipid that contributes in important ways to the peripheral regulation of food intake. When administered intraperitoneally, OEA is a potent satiety-inducing anorexiant in rats and mice [Nature 414 (2001) 209; Neuropsycopharmacology 28 (2003) 1311; Nature 425 (2003) 90]. In the present study, we show that oral administration of OEA in pH-sensitive enteric-coated capsules produces a profound and long-lasting inhibition of food intake in free-feeding rats. This effect is accompanied by a marked elevation in OEA levels in the small intestine, but not in brain or muscle.