A phase I study of pegylated liposomal doxorubicin hydrochloride (Caelyx) in combination with cyclophosphamide and vincristine as second-line treatment of patients with small-cell lung cancer

The purpose of this study was to determine the recommended phase II dose of liposomal doxorubicin (Caelyx ; Doxil in the United States) in combination with cyclophosphamide and vincristine for previously treated patients with good performance status with relapsed or refractory small-cell lung cancer. Twenty-one eligible patients were enrolled between November 1999 and September 2001 and received liposomal doxorubicin 25-40 mg/m2, cyclophosphamide 750-1000 mg/m2, and vincristine 1.2 mg/m2 intravenously (I.V.) every 21 days. At doses of liposomal doxorubicin 40 mg/m2, cyclophosphamide 750 mg/m2, and vincristine 1.2 mg/m2 I.V., 1 of 6 patients had dose-limiting neutropenia and fever in cycle 2 and 2 of 6 developed grade 3 hand-foot syndrome during cycle 3. Therefore, the recommended phase II doses are liposomal doxorubicin 35 mg/m2, cyclophosphamide 750 mg/m2, and vincristine 1.2 mg/m2 I.V. every 21 days. Antitumor activity was seen at all dose levels. This combination is well tolerated and has evidence of antitumor activity. A phase II evaluation is ongoing.     

Protocol for the evaluation of a decision aid for women with a breech-presenting baby [ISRCTN14570598]

Background  

There is now good evidence about the management options for pregnant women with a breech presentation (buttocks or feet rather than head-first) at term; external cephalic version (ECV) – the turning of a breech baby to a head-down position and/or planned caesarean section (CS). Each of these options has benefits and risks and the relative importance of these vary for each woman, subject to her personal values and preferences, a situation where a decision aid may be helpful.     

Effect of exogenous DMNPE-caged ATP on in vitro-matured bovine oocytes prior to parthenogenetic activation, fertilisation and nuclear transfer

Adenosine triphosphate (ATP) plays an important role during fertilisation of the mammalian oocyte through its ability to alter the frequency and duration of calcium oscillations. It has also been shown that higher ATP levels correlate with increased developmental competence in bovine and human oocytes. During somatic cell nuclear transfer (NT), the incoming nucleus is remodelled extensively, undoubtedly using a variety of ATP-dependent enzymes. The aim of the present study was to determine whether additional exogenous ATP influences activation of parthenogenetic (PA), in vitro-fertilised (IVF) or cloned (NT) in vitro-matured bovine oocytes. Blastocyst development and cell numbers in PA embryos were found to increase in a dose-dependent manner following the photorelease of 0, 50, 100, 500 and 1000 microm DMNPE-caged ATP (adenosine 5'-triphosphate, P3-(1-(4,5-dimethoxy-2-nitrophenyl)ethyl) ester, disodium salt). No cleavage was found following release of 2 and 5 mm DMNPE-caged ATP or with DMNPE-caged ATP (not photoreleased). There were also no differences in blastocyst rates or cell numbers between the control group and groups treated with caged, but not photoreleased, ATP. The addition of exogenous ATP before IVF or to NT couplets did not result in a significant increase in blastocyst development or cell number. Embryo transfer is necessary to determine whether exogenous ATP can positively affect reprogramming, resulting in higher cloned pregnancy rates or live-term births.     

A randomized, controlled comparison of the efficacy and tolerability of low and high doses of haloperidol in the treatment of first-episode psychosis

While haloperidol is still widely used in the treatment of psychoses, the optimal daily dose remains a topic of controversy, particularly in first-episode psychosis. Previous studies have suggested that doses as low as 2 mg/d may be effective, whereas others have indicated superiority for higher over lower doses. This double-blinded, randomized controlled study compared the efficacy and tolerability of 2 vs. 8 mg/d of haloperidol over 6 wk in 40 subjects with first-episode psychosis. Both treatments were equally effective in reducing the PANSS Total and subscale scores. The low dose of haloperidol was better tolerated, with fewer extrapyramidal side-effects, less frequent use of anticholinergic medication and smaller elevations in prolactin levels. Using a low dose of haloperidol is at least as effective as, and better tolerated than a high dose of haloperidol in the treatment of first-episode psychosis.     

High-grade vulval intraepithelial neoplasia (VIN 3): a retrospective analysis of patient characteristics, management, outcome and relationship to squamous cell carcinoma of the vulva 1989-1999

OBJECTIVES: To determine patient and disease characteristics, treatment patterns and long-term outcomes, in order to help direct management of patients with VIN 3, to examine the risk of development of cancer following a diagnosis of VIN 3 and the risk of recurrent disease requiring multiple treatment episodes, and to review patients with vulval cancer, in order to establish the relative prevalence of VIN 3 related vulval cancers. DESIGN: Retrospective chart review of 65 consecutive patients diagnosed with VIN 3 between 1989 and 1999. POPULATION OR SAMPLE: All patients diagnosed with VIN 3 at Christchurch Womens' Hospital (1 January 1989 to 31 December 1999) and Dunedin Public Hospital (1 January 1990 to 31 December 1999). MAIN OUTCOME MEASURES: Age at diagnosis, symptoms, medical history disease characteristics, treatment, outcome and follow-up. RESULTS: The median age at diagnosis was 38 years. Smokers were younger than non-smokers. Two-thirds had associated dysplasia of the lower genital tract, 43% had high-grade lesions. Seventy-nine per cent were symptomatic for a median of 9.5 months. All had macroscopically visible disease. Colposcopy and histology diagnoses correlated in 72% of cases. Treatment by local excision was undertaken in 84% of cases of which 65% had involved margins. Fifty-one per cent required further treatment, risk factors were positive margins and multifocal disease. Three developed micro-invasive cancer. CONCLUSIONS: Treatment by local excision is both diagnostic and therapeutic. Excision may reveal micro-invasive cancer, patients are usually symptomatic and VIN 3 has some potential to become invasive. Treated patients may develop microinvasive disease but frank invasion was not seen. The true rate of malignant progression in untreated patients remains unclear and radical surgery is rarely indicated. All patients require long-term follow up.     

A phase I pharmacokinetic and pharmacodynamic study of TKI258, an oral, multitargeted receptor tyrosine kinase inhibitor in patients with advanced solid tumors.

PURPOSE: To determine the maximum tolerated dose (MTD) dose-limiting toxicity, and pharmacokinetic and pharmacodynamic profile of TKI258 (formerly CHIR-258). EXPERIMENTAL DESIGN: A phase I dose escalating trial in patients with advanced solid tumors was performed. Treatment was initially as single daily doses on an intermittent 7-day on/7-day off schedule. Following a protocol amendment, a second schedule comprised, during cycle 1, 7-day on/7-day off treatment followed by 14 days of continuous daily dosing; subsequent cycles comprised 28 days of daily dosing. Pharmacokinetics and evaluation of phosphorylated extracellular signal-regulated kinase (ERK) in peripheral blood mononuclear cells were done during the first 28 days of each schedule. RESULTS: Thirty-five patients were treated in four intermittent (25-100 mg/d) and three continuous (100-175 mg/d) dosing cohorts. Observed drug-related toxicities were nausea and vomiting, fatigue, headache, anorexia, and diarrhea. Dose-limiting toxicities were grade 3 hypertension in one patient at 100 mg continuous dosing, grade 3 anorexia in a second patient at 175 mg, and grade 3 alkaline phosphatase elevation in a third patient at 175 mg. One patient had a partial response (melanoma) and two patients had stable disease >6 months. TKI258 pharmacokinetics were linear over the dose range of 25 to 175 mg. Five of 14 evaluable patients had modulation of phosphorylated ERK levels. CONCLUSIONS: The MTD was defined as 125 mg/d. Evidence of antitumor activity in melanoma and gastrointestinal stromal tumors warrants further investigation, and other phase I studies are ongoing. Further pharmacodynamic evaluation is required in these studies to evaluate the biological effects of TKI258.