ILF-3 is a regulator of the neural plate border marker Zic1 in chick embryos.

BACKGROUND: The neural crest is a multipotent cell type unique to the vertebrate lineage and capable of differentiating into a large number of varied cell types, including ganglia of the peripheral nervous system, cartilage, and glia. An early step in neural crest specification occurs at the neural plate border, a region defined by the overlap of transcription factors of the Zic, Msx, and Pax families. RESULTS: Here we identify a novel chick gene with close homology to double-stranded RNA-binding protein Interleukin enhancer binding factor 3 (ILF-3) in other species. Our results show that chick Ilf-3 is required for proper expression of the transcription factor, Zic-1, at the neural plate border. CONCLUSION: We have identified a novel chick gene and show it has a role in the correct specification of Zic-1 at the neural plate border.

Phase I study of pharmacologically based dosing of carboplatin with filgrastim support in women with epithelial ovarian cancer.

PURPOSE: The aim of this study was to increase the dose intensity of carboplatin in women with International Federation of Gynecology and Obstetrics (FIGO) Stage Ic-IV epithelial ovarian cancer with the use of granulocyte colony-stimulating factor (G-CSF; filgrastim; Amgen, Thousand Oaks, CA). PATIENTS AND METHODS: A phase I study of escalating target area under the curves (AUCs) of carboplatin with G-CSF (filgrastim) ws undertaken. The target AUCs were 5 mg/mL.min every 21 days for four cycles, 5 mg/mL.min every 14 days for four cycles, 7 mg/mL.min every 14 days for four cycles, 9 mg/mL.min every 14 days for four cycles, and 11 mg/mL.min every 14 days for four cycles. G-CSF was given at a dose of 5 microg/kg/d starting 24 hours after carboplatin administration and lasting until 24 hours before the next cycle and until day 14 after the last cycle. RESULTS: We were able to escalate to an AUC level of 9 mg/mL.min every 14 days for four cycles. At this dose, severe thrombocytopenia, that necessitated dosage delays, and failure to give subsequent cycles of carboplatin were observed. We then reduced the AUC level to 8 mg/mL.min every 14 days for four cycles. However, severe thrombocytopenia was also observed at this level. CONCLUSION: An AUC of 7 mg/mL.min every 14 days for four cycles is the maximum tolerated AUC level that can be achieved with G-CSF. Further escalations may be possible using either combinations of cytokines or peripheral stem-cell collections.

The EORTC clinical research coordinators group. European Organisation for Research and Treatment of Cancer.

The Clinical Research Coordinators Group (CRCG) is an umbrella organisation, compiled from four existing groups, namely the Oncology Nurses Group, the Data Management Group, the Radiation Technologists Group and the Early Clinical Studies Group Research Nurses. From the existing steering committees, a new board was formed and consists of two members per group. The CRCG will function as an independent group within the EORTC. The CRCG will create conditions and standards for implementing and conducting clinical protocols according to Good Clinical Practice.

Pharmacological study of paclitaxel duration of infusion combined with GFR-based carboplatin in the treatment of ovarian cancer.

PURPOSE: To determine the effect on systemic pharmacology and clinical toxicity of dose and mode of administration of paclitaxel combined with carboplatin in the treatment of ovarian cancer. PATIENTS AND METHODS: A total of 18 patients were treated with a dose of carboplatin determined by GFR, to attain a target AUC of 6 or 7 mg/ml x min. The paclitaxel dose was 175 or 200 mg/m2 administered over approximately 1 or 3 h. The duration of infusion was randomized, crossing over to the alternative treatment for the second course. Blood samples were analysed for carboplatin, paclitaxel and for the excipients of the paclitaxel formulation, ethanol and Cremophor. RESULTS: Overall the three-weekly schedule of administration of the combination of carboplatin and paclitaxel was well tolerated. There were no clinical differences in the toxicities observed between courses where a 1-h infusion was used compared with those with a 3-h infusion. The target AUC of carboplatin was achieved (mean +/- SD 114 +/- 20% of target). Analysis of paclitaxel pharmacokinetics did not show a difference in the AUC or time above a pharmacological threshold for the two infusion durations. The peak concentration of paclitaxel obtained at the end of the infusion (9.1 vs 4.5 microg/ml), and the plasma ethanol concentration (40.0 vs 20.5 mg/dl) were higher following the shorter duration infusion. Peak concentrations of Cremophor were not different. CONCLUSION: The combination of paclitaxel at a dose of 175 mg/m2 and carboplatin at a target AUC of 6-7 mg/ml min can safely be administered every 3 weeks. Also, a 1-h infusion of paclitaxel has no acute clinical disadvantage over a 3-h infusion and these durations of administration are pharmacologically equivalent.

An unusual cause of postoperative detrusor overactivity.

Fallopian tube prolapse through a ruptured vagina is a rare, but well-documented, gynaecological condition. The majority of cases reported in the literature complicated vaginal hysterectomy and presented with vaginal bleeding and pelvic pain. We report a case after abdominal hysterectomy, which presented with urinary symptoms, an unreported presentation, and was managed successfully via the vaginal route. An update on the cases reported in the literature is also presented.

Phase I study of temozolomide plus paclitaxel in patients with advanced malignant melanoma and associated in vitro investigations.

The purpose of this study was to determine activity of temozolomide combined with paclitaxel or epothilone B in vitro, and to investigate the combination of temozolomide with paclitaxel in a Phase I clinical trial. Melanoma cell lines A375P and DX3 were treated with temozolomide and either paclitaxel or epothilone B. Combination indices were determined to assess the degree of synergism. In a clinical study, 21 patients with malignant melanoma were treated with increasing doses of temozolomide (orally, days 1-5), in combination with a fixed dose of paclitaxel (i.v. infusion day 1), followed by dose escalation of the latter drug. Cycles of treatment were repeated every 3 weeks. Pharmacokinetics of both agents were determined on day 1, with temozolomide pharmacokinetics also assessed on day 5. All three compounds were active against the melanoma cell lines, with epothilone B being the most potent. There was a strong degree of synergism between temozolomide and either paclitaxel or epothilone B. In the clinical study, no pharmacokinetic interaction was observed between temozolomide and paclitaxel. Dose escalation of both drugs to clinically active doses was possible, with no dose-limiting toxicities observed at 200 mg m(-2) day(-1) temozolomide and 225 mg m(-2) day(-1) paclitaxel. There were two partial responses out of 15 evaluable patients. One patient remains alive and symptom-free at 4 years after treatment. Temozolomide and paclitaxel may be administered safely at clinically effective doses. Further evaluation of these combinations in melanoma is warranted.

Changes in methacholine induced bronchoconstriction with the long acting beta 2 agonist salmeterol in mild to moderate asthmatic patients.

BACKGROUND: Beta-2 agonists protect against non-specific bronchoconstricting agents such as methacholine, but it has been suggested that the protection afforded by long acting beta 2 agonists wanes rapidly with regular treatment. METHODS: The changes in airway responsiveness were investigated during and after eight weeks of regular treatment with salmeterol 50 micrograms twice daily in 26 adult asthmatic patients, 19 of whom were receiving maintenance inhaled corticosteroids. The study was of a randomised, placebo controlled, double blind design. Airway responsiveness to methacholine was measured as PD20 by a standardised dosimeter technique 12 hours after the first dose, at four weeks and eight weeks during treatment (12 hours after the last dose of test medication), and at 60 hours, one week and two weeks after stopping treatment. RESULTS: There were no significant differences between the baseline characteristics of the two groups. A significant improvement in PD20 was seen at all points during treatment with salmeterol compared with the placebo group, with no significant fall off with time. PD20 measurements returned to baseline values after cessation of treatment with no significant difference from the placebo group. CONCLUSIONS: Salmeterol gave significant protection against methacholine induced bronchoconstriction 12 hours after administration. This protection was of small magnitude, but there was no significant attenuation with eight weeks of regular use and no rebound increase in airway responsiveness on stopping treatment in a group of moderate asthmatic patients, the majority of whom were receiving inhaled corticosteroids.

Preparing the male urethra for transurethral procedures.

The antiseptic and analgesic effectiveness of different preparations of lignocaine gel used prior to flexible cystoscopy were studied in patients recruited over a 12-month period. This random study involved 106 patients in four groups. There appeared to be no difference in bacterial colonisation of the urethra between the groups. Urethral analgesia was improved when higher volumes of gel were used. It was concluded that high-volume gel preparations (> 20 ml) with no antiseptic provided optimal conditions for flexible cystoscopy.

Adverse effects of a single dose of (+)-sotalol in patients with mild stable asthma.

AIMS: To investigate the effect of (+)-sotalol, which is not thought to possess clinically significant beta-adrenoceptor blocking activity, on airway responsiveness in subjects with mild asthma. METHODS: A placebo controlled, double-blind, single dose, cross over study, evaluating the effects of oral (+)-sotalol 300 mg and oral (+/-)-sotalol 240 mg, on airway responsiveness, FEV1, and heart rate in 18 asthmatic volunteers with quantifiable levels of airway responsiveness. RESULTS: Compared with placebo, (+)-sotalol induced a significant increase in airway responsiveness, and a significant decrease in FEV1, but there was no significant change in heart rate. Following (+/-)-sotalol there was no significant effect on airway responsiveness, but there were significant decreases in FEV1 and heart rate. In one subject both (+)-sotalol and (+/-)-sotalol provoked a 49% decrement in FEV1, and in another there were decrements of 20% and 18%, respectively. CONCLUSIONS: Despite theoretical considerations, it cannot be assumed that (+)-sotalol is safe in patients with asthma.

The duration of action of inhaled formoterol dry powder.

The duration of action of formoterol inhaled as a dry powder formulation is compared with placebo and a reference treatment of salbutamol dry powder in patients with bronchial asthma. This single-centre, double-blind, cross-over study recruited 23 outpatients with clinically stable asthma. These patients were treated with 12 micrograms formoterol, 400 micrograms salbutamol or placebo in a randomly allocated sequence, with at least 2 days between treatments. Forced expiratory volume in 1s of expiration (FEV1) was measured at specified time points from 15 min to 15 hours post-treatment. Formoterol produced significantly higher values of FEV1 at the primary endpoint of 12 hours compared with placebo and salbutamol. No differences between FEV1 values were seen for the active treatments of formoterol and salbutamol for the first 5 hours post-inhalation. Formoterol was significantly superior to placebo at all time points, whereas salbutamol was significantly superior to placebo for the first 5 hours. This study demonstrates that formoterol, when given as a dry powder inhalation, has a significantly longer duration of acute bronchodilator action than 400micrograms salbutamol inhaled as a dry powder. The duration of action of formoterol of at least 12 hours seen in this study is at least as long as that reported following administration from a metered dose inhaler (MDI) at the same dose level. The study also demonstrates that 12micrograms formoterol dry powder is well tolerated by patients.

Topotecan in combination with carboplatin: phase I trial evaluation of two treatment schedules.

BACKGROUND: Topotecan and cisplatin combinations have shown schedule-dependent toxicity, which may in part be due to cisplatin nephrotoxicity. As carboplatin is less nephrotoxic and increasingly replacing cisplatin in clinical practice, the aim of this study was to define the optimal sequence and dose for topotecan in combination with carboplatin. PATIENTS AND METHODS: Two parallel phase I trials, with pharmacokinetic studies, were conducted administering carboplatin on day 1 with topotecan on days 1-5 (schedule A) or days 8-12 (schedule B). repeated every 3 weeks. RESULTS: Twenty-one patients were treated over two dose levels, carboplatin AUC 4 [glomerular filtration rate (GFR) calculated from 51Cr-EDTA clearance] with topotecan 0.5 or 0.75 mg/m2. At the first dose level, six patients were evaluable for each schedule. With schedule A, from 34 cycles, there were two dose reductions and 10 treatment delays due to myelosuppression. With schedule B from 25 cycles, there was one reduction and 10 delays. At dose level 2, both patients in schedule A had dose-limiting neutropenia. In contrast, there was no dose-limiting toxicity with schedule B in six patients, although the majority of cycles were delayed. CONCLUSION: The combination of topotecan and carboplatin using these 3-weekly schedules lead to significant myelotoxicity with attendant dose reductions and delays; the optimal scheduling of these agents remains to be defined.