Assessment of tumor angiogenesis as a prognostic factor of survival in patients with oligodendroglioma.

According to World Health Organization (WHO) and Daumas-Duport grading systems, progression of oligodendrogliomas (ODGs) to a higher grade (WHO grade III, grade B) is associated with increased angiogenesis. Based on multivariate assessment of molecular, pathological, and radiological parameters, we further assessed the influence of tumor angiogenesis on tumor progression and patient survival. Patients with a diagnosis of ODG, consecutively treated in a single institution, were reviewed and reclassified according to WHO and Daumas-Duport grading systems. MRI scans were reviewed to assess contrast enhancement and necrosis. Tissue sections were used for pathology review and to evaluate immunostaining of vascular endothelial growth factor (VEGF), vascular endothelial growth factor receptor (VEGF-R), Ki-67, and CD34. Multivariate analysis was performed to assess the impact of tumor angiogenesis-related pathological and radiological factors on patient survival. One hundred thirty-four patients with pure ODG were included in this study. Multivariate analysis identified four independent poor prognostic factors: necrosis, absence of seizure, increased vascularization, and age >55 years. A subgroup of patients with tumor necrosis, increased vascularization, and absence of seizures had a significantly worse outcome than predicted, with a median overall survival of 14.2 months. VEGF expression was significantly higher in this subgroup and correlated with disease progression regardless of histologic grade. Based on the presence of radiological or pathological necrosis, contrast enhancement or endothelial hyperplasia, and absence of seizures, a high risk group of ODG can be identified with significantly worse overall survival. Also, VEGF over-expression in ODG constitutes an early marker for predicting tumor progression.

Desloratadine relieves nasal congestion and improves quality-of-life in persistent allergic rhinitis.

BACKGROUND: Symptoms of allergic rhinitis (AR), particularly nasal congestion, can impair quality-of-life (QoL). However, only a modest correlation exists between these symptoms and Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) scores, suggesting that both be evaluated for a complete assessment of health. METHODS: Subjects with a > or =2-year history of moderate-to-severe AR to dust mite or cat dander were randomized to desloratadine 5 mg/day (n = 293) or placebo/day (n = 291) for 28 days. Primary endpoint was change from baseline in a.m./p.m. nasal congestion score. Secondary outcomes included change from baseline in total nasal symptom score, individual symptom scores and RQLQ scores (completed on days 1, 7, and 28). RESULTS: The Allergic Rhinitis and its Impact on Asthma criteria for persistent allergic rhinitis (PER) were fulfilled by 99% of subjects in the placebo arm. Between-treatment difference in a.m./p.m. nasal congestion score, observed from day 8 onward, significantly favored desloratadine (P = 0.0003). Desloratadine significantly improved a.m./p.m. nasal congestion and RQLQ scores after 1 week and at treatment end (P < 0.05). Improvements in 5 of 7 RQLQ domain scores exceeded the minimal important difference. On days 7 and 28, desloratadine was also significantly superior to placebo in mean change from baseline in a.m./p.m. total nasal symptom score and rhinorrhea score (both P < or = 0.01). Symptomatic benefit was primarily driven by improvement in nasal congestion and rhinorrhea. CONCLUSIONS: Desloratadine 5 mg/day significantly improved symptoms associated with PER, including nasal congestion, and provided significant improvement in QoL after 1 week of treatment.

Initial chemotherapy in gliomatosis cerebri.

BACKGROUND: Because of the diffuse nature of gliomatosis cerebri (GC), surgery is not suitable, and large field radiotherapy carries the risk of severe toxicity. In this setting, initial chemotherapy warrants further investigation. METHODS: The authors treated 63 consecutive patients with GC with initial chemotherapy consisting of either PCV (procarbazine, 60 mg/m2 on days 8 to 21; CCNU, 110 mg/m2 on day 1; and vincristine, 1.4 mg/m2 on days 8 and 29) or temozolomide (TMZ; 150 to 200 mg/m2 for 5 days every 4 weeks). There were 40 men and 23 women, with a median age of 48 years (range, 17 to 74 years) and a median Karnofsky performance status of 90 (range, 50 to 100). GC was initially present at diagnosis in 49 patients (primary GC), whereas 14 patients with a circumscribed glioma at onset developed secondary GC after a median follow-up period of 5.11 years. GC was classified based on the predominant tumor cells as astrocytic, oligodendroglial, or mixed GC. RESULTS: Seventeen patients received 1 to 6 cycles (median, 5) of PCV, and 46 received 2 to 24 courses (median, 13) of TMZ. Grade 3 to 4 hematologic toxicity was seen in 4 of 17 (23.5%) patients treated with PCV and in 4 of 46 (8.6%) of those treated with TMZ. Clinical objective responses were observed in 21 of 63 (33%) patients, and radiologic responses were seen in 16 of 62 (26%), with no significant difference between the two regimens. For all patients combined, the median progression-free survival (PFS) and overall survival (OS) were 16 months and 29 months, respectively. Regardless of the chemotherapeutic regimen, oligodendroglial GC had a better prognosis than astrocytic and oligoastrocytic GC in terms of PFS (p < 0.02) and OS (p < 0.0001). CONCLUSION: Initial chemotherapy is useful for some patients with gliomatosis cerebri. Temozolomide is well tolerated and appears to be a valuable alternative to procarbazine-CCNU-vincristine, especially for those with slow-growing, low-grade GC.

Isepamicin in intensive care unit patients with nosocomial pneumonia: population pharmacokinetic-pharmacodynamic study.

A population approach was used to determine isepamicin pharmacokinetics in 196 intensive care unit patients treated for nosocomial pneumonia with isepamicin and a broad-spectrum beta-lactam. Patients were randomized in four groups with respect to the following isepamicin dosing regimens: (i) 15 mg/kg od for 5 days or (ii) 10 days, (iii) 25 mg/kg on the first day followed by 15 mg/kg od for 4 days or (iv) 9 days. A total of 1489 serum isepamicin concentrations were measured (median, eight per patient; range, 1-18). Mean +/- S.D. 1 h-peak levels at day 1 were 76 +/- 32 mg/L after the 25 mg/kg dose (n = 85) and 43 +/- 15 mg/L after the 15 mg/kg dose (n = 99). A bicompartmental model was fitted to the data by a mixed-effect modelling approach. Isepamicin clearance was related to age, bodyweight and serum creatinine level. Central volume of distribution was related to bodyweight. Pharmacokinetic parameters were independent of the dosage in the range 15-25 mg/kg and were not different in the patients treated for 5 or 10 days. Bayesian estimates of individual pharmacokinetic parameters were used to calculate various surrogate markers of isepamicin exposure to be tentatively correlated with clinical outcome and nephrotoxicity. No correlation was found between peak, AUC or their ratio with MIC and clinical efficacy. A weak correlation was found between the increase of serum creatinine level (day 1 versus day 5) and isepamicin 24 h trough level at day 1 (R2 = 0.10). These data do not favour a systematic therapeutic monitoring of isepamicin in intensive care unit patients, at least with the doses and antibiotic combinations used in this study.

Changes in skin-test reactivity do not correlate with clinical efficacy of H1-blockers in seasonal allergic rhinitis.

New-generation H1-blockers may possess antiallergic properties, and their effect may differ, depending on the target organ. A double-blind, placebo-controlled, parallel-group study was carried out during the pollen season to compare the clinical effect on nasal and conjunctival symptoms of astemizole (10 mg o.d.) and loratadine (10 mg o.d.) with their effect on skin-test reactivity to allergen and histamine. Thirty-eight patients (12-56 years of age) were studied. Nasal and ocular symptoms were recorded daily from days 4 to 7. Skin prick tests with serial concentrations of allergens and one concentration of histamine were carried out before and at the end of the 7-day treatment period. Parallel-line bioassay, analysis of variance, and covariance were used to analyze skin test data. Loratadine and astemizole significantly decreased symptoms from baseline (P < 0.004 and P < 0.006). Skin-test reactivity to allergen and histamine was more profoundly decreased by astemizole than loratadine. The histamine covariant was more important in the allergen effect of astemizole than in that of loratadine. Two H1-blockers having the same clinical effect on nasal and ocular symptoms during the pollen season have totally different effects on skin-test reactivity. Skin-test reactivity to allergen or histamine is not predictive of the clinical efficacy of H1-blockers during seasonal allergic rhinitis.

Adjunct effect of loratadine in the treatment of acute sinusitis in patients with allergic rhinitis.

H1-blockers are often added to the standard treatment of acute sinusitis, but this is not supported by a controlled study. A multicentric, randomized, double-blind, placebo-controlled, parallel-group study was done in 139 allergic patients (15-65 years) to assess the adjunct efficacy of loratadine in acute exacerbation of rhinosinusitis. Sinusitis was diagnosed by symptoms and confirmed by rhinoscopy and sinus radiograph. Allergy was characterized by skin tests, RAST, and history. Patients were treated with antibiotics (14 days), oral corticosteroids (10 days), and loratadine (10 mg OD) or placebo (28 days). Treatment efficacy was assessed over 28 days by symptom scores quoted daily by patients. Physicians also rated total symptom scores at entry and at day 28. At entry, both groups had similar symptoms. Placebo-treated patients improved significantly, but patients who received loratadine had a significantly greater improvement in sneezing (P = 0.003) after 14 days, and in nasal obstruction (P = 0.002) after 28 days. Physicians found that patients receiving loratadine were significantly improved compared to placebo patients (P = 0.0125). Loratadine in addition to standard therapy was found to improve the control of some symptoms of sinusitis.

Population pharmacokinetic study of isepamicin with intensive care unit patients.

The pharmacokinetics (PK) of isepamicin, a new aminoglycoside, were studied in 85 intensive care unit (ICU) patients and were compared with those observed in 10 healthy volunteers. A parametric method based on a nonlinear mixed-effect model was used to assess population PK. Isepamicin was given intravenously over 0.5 h at dosages of 15 mg/kg once daily or 7.5 mg/kg twice daily. The data were fitted to a bicompartmental open model. Compared with healthy volunteers, the mean values of the PK parameters were profoundly modified in ICU patients: elimination clearance was reduced by 48%, the volume of distribution in the central compartment (Vc) was increased by 50%, the peripheral volume of distribution was 70% higher, the distribution clearance was 146% lower, and the elimination half-life was ca. 3.4 times higher. The interindividual variability in PK parameters was about 50% in ICU patients. Five covariates (body weight [BW], simplified acute physiology score [SAPS], temperature, serum creatinine level, and creatinine clearance [CLCR]) were tentatively correlated with PK parameters by multivariate linear regression analysis with stepwise addition and deletion. The variability of isepamicin clearance was explained by three covariates (BW, SAPS, and CLCR), that of Vc was explained by BW and SAPS, and that of the elimination half-life was explained by CLCR and SAPS. Simulation of the concentration-versus-time profile for 500 individuals showed that the mean peak (0.75 h) concentration was 18% lower in ICU patients than in healthy volunteers and that the range in ICU patients was very broad (28.4 to 95.4 mg/liter). Therefore, monitoring of the isepamicin concentration is in ICU patients is mandatory.

A randomized, controlled trial of interferon alfa-2b alone and with simultaneous prednisone for the treatment of chronic hepatitis B. French Multicenter Group.

The aim of the study was to evaluate the safety and effectiveness of interferon alpha-2b with or without concomitant corticosteroid treatment in patients with chronic hepatitis B. Fifty-six patients were randomly allocated to two treatment groups. Group I (n = 25) received interferon alpha-2b (INTRON A, Schering-Plough Corporation) 5 million unit subcutaneously, three times a week for 24 weeks. Group II (n = 31) received interferon according to the same protocol and prednisolone in decreasing doses of 60, 40, 20 mg for 6 weeks. The two groups were well matched for demographic, biochemical, virological and histologic features. Both groups were followed up for 24 weeks after treatment. No statistical difference was observed between the two groups at the end of the follow-up in alanine aminotransferase values, HBV DNA negativation, HBeAg loss, anti-HBe seroconversion and the Knodell score. The greater proportion of HBsAg clearance in the combination group, particularly in patients with low alanine aminotransferase values, was, however, not significant. In patients with low alanine aminotransferase values, only the Knodell score was significantly decreased in patients treated with interferon and prednisolone. The only factor which was found to be a predictor of response was the assumed duration of hepatitis. These findings showed that a concomitant short administration of corticosteroids during the first weeks of interferon therapy did not improve results with interferon alone.

[Clinical effectiveness and tolerance of loratadine versus cetirizine in the treatment of seasonal allergic rhinitis]. / Efficacité clinique et tolérance de la Loratadine versus Cétirizine dans le traitement de la rhinite allergique saissonnière.

A double blind multicentre study of seasonal rhinitis (108 patients) has compared Loratadine and Cetirizine. The results of clinical scores are significantly good for both products. Only tolerance is different and in favour of Loratadine, since sleepiness was found in 9.5% of patients treated with Cetirizine, and 3.6% with Loratadine.

Selegiline in de novo parkinsonian patients: the French selegiline multicenter trial (FSMT).

The French selegiline multicenter trial was conducted in 1990 to test the possibility to improve disability of de novo parkinsonian patients (P.P.) during the first three months of treatment with selegiline (S) (10 mg/day) monotherapy. 93 P.P. were included in this double-blind, randomized, placebo controlled, clinical trial, in which 13 centers participated. Both parallel groups were followed up from inclusion (D0) to D30, D60 and D90. Drug efficacy was judged with Hoehn and Yahr (HY), Hamilton Depression Rating Scale (HDRS), Unified Parkinson's Disease Rating Scale (UPDRS), Schwab and England scores, decision to introduce levodopa and selfassessment. Biological and clinical parameters (cardio- vascular, weight, side-effects reports) were assessed for tolerability. 84 P.P. (38 P, 46 S) were evaluable for efficacy at D90. When considering the main parameters, S appears superior to placebo: HY scores (p less than 0.001), global UPDRS scores (p less than 0.001) and UPDRS subscores: mental (p less than 0.001), daily living activities (p less than 0.01), motor activities (p less than 0.01). Depressive scores (HDRS) are significantly improved only at D90 (p = 0.005). Levodopa therapy was introduced in 45% of the cases in S groups versus 18.4% in P group. Global impression of efficacy was largely in favor of S; failure was noted in half of the cases in P group and only in 1/5th of the cases in S group. Side-effects were rare and minor. S 10 mg/day monotherapy is statistically superior to placebo in improving de novo P.P. during the first three months treatment. Motor symptoms rapidly improve; mood is only modified after 3 months. S appears to be well tolerated. S may be considered as a good candidate for the initial treatment of P.P.

Chronokinetic study of netilmicin in man.

Netilmicin 1.5 mg/kg body weight was administered intravenously every 8 h for 2 days to 8 patients with normal renal function. Significant elevation of mean and trough plasma concentrations was found at 05.00 h and 09.00 h. This was considered to be due to circadian variation, with possible accumulation during the night. The clinical importance of this phenomenon in relation to the development of aminoglycoside toxicity awaits further investigation.