Leucovorin, 5-fluorouracil,and gemcitabine: A phase I study

Gemcitabine is a chemotherapy agent with efficacy in the treatment of lung, pancreas, bladder and breast cancer. It inhibits DNA synthesis by interfering with cytidine triphosphate production and also inhibits the activity of ribonucleotide reductase. Gemcitabine may potentiate fluorouracil's inhibition of thymidylate synthase. This inhibition would be expected to be sequence dependent, occurring only if gemcitabine were administered following fluorouracil (5FU).The combination of leucovorin, 5-FU, and gemcitabine was assessed in this phase I trial. Eligibility requirements included refractory solid tumor malignancy; adequate hematologic, renal and hepatic reserve; no prior therapy with the combination of leucovorin and 5FU, or with gemcitabine; ECOG performance status 0–2, and signed informed consent.Eleven men and nine women were eligible. The median age was 52.5 years and the median performance status was 1. All but three patients had prior chemotherapy. The starting doses were leucovorin 20 mg/m², 5FU 255 mg/m² and gemcitabine 600 mg/m². 5FU and gemcitabine were escalated in tandem to 340 mg/m² and 800 mg/m² and thereafter to 425 mg/m² and 1000 mg/m², respectively. Gemcitabine administration always followed that of 5FU by 30 minutes. The median number of cycles was 2 (range 1–32). Two patients at the starting dose had disease progression within the first cycle with one death on day 28. One patient with cholangiocarcinoma had a partial response and remained on study for 40 months. There were no other responses.The maximum tolerated dose is leucovorin 20 mg/m², 5FU 340 mg/m², and gemcitabine 800 mg/m². The impact of drug sequence remains undetermined.     

Including a time-of-year effect in the analysis of a matched case-control study

Motivated by a matched case-control study to investigate potential risk factors for meningococcal disease amongst adolescents, we consider the analysis of matched case-control studies where disease incidence, and possibly other risk factors, vary with time of year. For the cases, the time of infection may be recorded. For controls, however, the recorded time is simply the time of data collection, which is shortly after the time of infection for the matched case, and so depends on the latter. We show that the effect of risk factors and interactions may be adjusted for the time of year effect in a standard conditional logistic regression analysis without introducing any bias. We also show that, if the time delay between data collection for cases and controls is constant, provided this delay is not very short, estimates of the time of year effect are approximately unbiased. In the case that the length of the delay varies over time, the estimate of the time of year effect is biased. We obtain an approximate expression for the degree of bias in this case.     

Comparative Efficacy of Once-Daily Umeclidinium/Vilanterol and Tiotropium/Olodaterol Therapy in Symptomatic Chronic Obstructive Pulmonary Disease: A Randomized Study

Introduction

We report the results of the first direct comparison of the once-daily fixed-dose long-acting muscarinic antagonist/long-acting β₂-agonist (LAMA/LABA) combinations umeclidinium/vilanterol (UMEC/VI) and tiotropium/olodaterol (TIO/OLO) in patients with COPD.

Methods

This was a randomized, two-period crossover open-label study in symptomatic patients with COPD [age 40 years or older, postbronchodilator forced expiratory volume in 1 s (FEV₁) of 70% or less and 50% or more of predicted normal values, and modified Medical Research Council Dyspnoea Scale score of 2 or greater] not receiving inhaled corticosteroid therapy. Patients were randomized to receive UMEC/VI (62.5/25 µg once daily) via a multidose dry powder inhaler (ELLIPTA) followed by TIO/OLO (5/5 µg once daily) via a soft mist inhaler (Respimat), each for 8 weeks with an interim 3-week washout or vice versa. The primary end point was the change from baseline in trough FEV₁ at week 8 with a noninferiority margin of ? 50 mL in the per-protocol (PP) population. The incidence of adverse events was also assessed.

Results

In total, 236 patients (mean age 64.4 years, 60% male) were included in the intent-to-treat population and 227 were included in the PP population. UMEC/VI treatment was noninferior in the PP population and superior in the intent-to-treat population to TIO/OLO treatment with regard to trough FEV₁ at week 8 [FEV₁ change from baseline 180 mL vs 128 mL; difference 52 mL (95% confidence interval 28–77 mL); p < 0.001]. Patients receiving UMEC/VI had twofold increased odds of experiencing a clinically meaningful increase (100 mL or more) from baseline in trough FEV₁ at week 8 compared with patients receiving TIO/OLO (odds ratio 2.05; 95% confidence interval 1.34–3.14). Adverse events occurred in 25% of patients in the UMEC/VI group and in 31% of patients in the TIO/OLO group.

Conclusion

In this first direct comparison of two once-daily fixed-dose LAMA/LABA combinations, superiority was observed for the primary end point of trough FEV₁ at week 8 with UMEC/VI compared with TIO/OLO in patients with symptomatic COPD. Both treatments had similar safety profiles. These findings confirm the results of previous indirect LAMA/LABA comparisons, and show that an efficacy gradient exists within the LAMA/LABA class.

Trial Registration

ClinicalTrials.gov identifier NCT02799784.

Funding

GlaxoSmithKline.

     

The phosphocholine and glycerophosphocholine content of an oestrogen-sensitive rat mammary tumour correlates strongly with growth rate

An oestrogen sensitive rat mammary tumour was grown in two groups of female and one group of male hooded rats. The male group and one of the female groups were supplemented with oestrogen. The tumours grew most rapidly in the female supplemented group. When the tumours reached 1.5 cm in diameter they were harvested and the cell cycle distribution and number of cells actively synthesising DNA (bromodeoxyuridine (BrdU) labelling index) determined in each case. Chemical extracts were prepared from each tumour and the concentration of phosphorus-containing metabolites determined using high resolution NMR spectroscopy. The concentration of phosphocholine was found to correlate strongly with the number of cells in S-phase and the number of cells labelled with BrdU, whilst a highly significant negative correlation was observed between these two parameters and glycerophosphocholine. The concentration of phosphoethanolamine did not correlate with either of these measures of proliferation rate. The concentration of glycerophosphorylethanolamine showed a weak negative correlation with the number of cells in S-phase.     

Proliferative behaviour of an oestrogen sensitive rat mammary tumour: evidence for a paracrine interaction between tumour and stroma.

An oestrogen-sensitive rat mammary tumour (OES HR1) has been grown in normal female rats and in female and male rats supplemented with oestrone. In some rats, after the tumour was established, both exogenous and endogenous sources of oestrogen were removed--a treatment which inhibited further growth of the tumour. The proliferative characteristics of the tumours were measured by injecting the rats with deoxybromouridine (BrdU) 4 h before removing the tumour. Extracted nuclei were reacted with anti-BrdU and the labelling index and DNA content measured by flow cytometry. A correlation between the number of (diploid) host cells present and the number of (aneuploid) tumour cells in S-phase of the cell cycle was observed. This result suggests that there are paracrine interactions between tumour and host cells. We also observed that, on oestrogen ablation, the labelling index was significantly reduced while the percentage of cells in S-phase changed far less. The demonstration that there are cells in S-phase which are not proliferating highlights a possible problem with the measurement of proliferation in human tumours from a DNA histogram.     

Uptake and distribution of L-3-[I-125] Iodo-α-methyl tyrosine in experimental rat tumours: comparison with blood flow and growth rate

Radiolabelled amino acids combined with positron emission tomography (PET) show promise for the accurate delineation of viable tumour extent and may also provide a rapid and sensitive indicator of response to therapy. We have investigated the potential use of the radioiodinated amino acid analogue L-3-iodo--methyl tyrosine (IMT) for these purposes using experimental tumours in hooded rats. Preliminary studies using HSN tumours and IMT labelled with iodine-125 demonstrated maximum tumour uptake at 15 min post injection although an improved tumour-to-brain ratio was seen at 24 h due to the relatively poor retention of IMT in normal brain. Brain uptake of IMT was also found to be substantially reduced by competition with another large neutral amino acid phenylalanine; however, relatively less effect was seen in tumour, and in skeletal muscle no change in IMT uptake was observed. Quantitative autoradiography revealed no sign of heterogeneity in tumour IMT uptake: good penetration was seen even in poorly vascularised regions as confirmed by endothelial immunohistochemistry. Similar levels of IMT uptake were found in the OES.HR1 tumour during growth supplemented by exogenous oestrogen. Following arrest of tumour growth by removal of the oestrogen stimulus, IMT uptake was seen to fall from 1.7% to 1.0% of the injected dose per gram: this was matched by a fall in tumour blood flow as estimated by technetium-99m hexamethylpropylene amine oxime distribution. It appears that IMT uptake is more strongly influenced by blood flow than cell proliferation and that intratumoural distribution of IMT is principally determined by diffusion. Correspondence to: P. Carnochan     

Behavioral function effects on intervention acceptability and effectiveness for self-injurious behavior

A variety of variables have been found to augment perceived social validity of behavioral interventions. In the present study, potential effects of behavioral function were evaluated. Sixty students inexperienced in work with people with mental retardation, and 60 experienced staff watched one of two carefully matched acted videos depicting self-injury maintained by attention or escape from task demands. Participants were also told whether the self-injury depicted typically led to mild or severe consequences for the person filmed. Participants rated six interventions in terms of their acceptability and effectiveness for the behavior depicted. A hierarchy of acceptability was replicated: reinforcement-based procedures were rated as more acceptable and effective. There were also effects of behavior severity and rater experience. However, few effects of behavioral function were found. Potential implications of staff undifferentiated attitudes towards functional treatments are discussed.     

Tolerability of Fluticasone Furoate/Vilanterol Combination Therapy in Children Aged 5 to 11 Years With Persistent Asthma

Background

Asthma is a chronic disease afflicting millions of children worldwide. Short-acting β₂-agonist reliever medications and inhaled corticosteroid (ICS) maintenance therapies are effective treatments; however, many children remain uncontrolled with short-acting β₂-agonist and ICS treatment, in which case guidelines recommend adding a long-acting β₂-agonist.

Objective

We sought to investigate the safety profile, tolerability, and pharmacokinetic (PK) and pharmacodynamic (PD) properties of the long-acting β₂-agonist vilanterol (VI) combined with the ICS fluticasone furoate (FF) administered via the ELLIPTA dry powder inhaler (GlaxoSmithKline, London, United Kingdom) in children aged 5 to 11 years with persistent asthma.

Methods

In this randomized, double-blind, repeated-dose, 2-way crossover study, data from 8- to 11-year-old children with asthma were reviewed before those from 5- to 7-year-old children with asthma. Patients received once-daily FF/VI, 100/25 µg, or FF, 100 µg, in the morning for 14 days, followed by a ≥7-day washout period before switching to the other treatment for 14 days; the study duration was ≤11 weeks. Primary end points were adverse events (AEs), clinical laboratory measurements, peak expiratory flow, maximum heart rate, blood pressure, and electrocardiographic parameters. Secondary end points comprised PK (AUC_0–4, C_max) and PD (serum potassium [0–4 hours], serum cortisol [0–12 hours], and glucose [0–4 hours]) parameters on day 14.

Results

Twenty-six children were randomized (58% boys; mean age, 8.1 years). No clinically significant changes in the primary end points were observed. Five patients reported 4 and 2 AEs with FF/VI and FF therapy, respectively. After FF/VI or FF treatment, the geometric mean ratios (90% CIs) for FF AUC_0–4 (1.02 [0.86–1.22]) and FF C_max (0.98 [0.65–1.48]) were similar. For serum glucose (0–4 hours) concentration, a difference of 0.50 mM (95% CI, 0.19–0.82 mM) was observed for FF/VI versus FF; no differences were observed for other PD parameters. No AEs were judged to be serious or treatment related. The PK profile of FF did not seem to be altered by VI and was not affected by age or sex. The significance of an increased serum glucose level is difficult to judge as measurements were taken from nonfasted patients. Results can be compared only with active treatment, and the ability to generalize is limited by the small number of patients in this single-center study.

Conclusions

Once-daily repeated dosing of FF/VI, 100/25 µg, using the ELLIPTA dry powder inhaler was as well tolerated as FF, 100 µg, in this small, selected population of 5- to 11-year-old, mostly white/caucasian children with persistent asthma.     

Breastfeeding and problematic integration: results of a focus-group study

This article reports on a subset of data from nine focus groups. Participants included new and expectant mothers and their partners, friends, and relatives. The larger goal of the focus groups was to understand local infant-feeding practices of mothers in our region. The subset of data reported in this article pertains to breastfeeding failure. The experience of breastfeeding failure, as described by participants in this study, is analyzed through the lens of Babrow's (1992) concept of problematic integration.     

Teaching undergraduate medical students Child and Adolescent Psychiatry (CAP): a Delphi study on curriculum content

Background

The prevalence of psychiatric disorders in children and young people is high but despite this, many doctors have difficulty identifying and managing psychiatric disorders presenting in this age group. The purpose of this study was to determine appropriate curriculum content in Child and Adolescent Psychiatry (CAP) for a Graduate Entry Medicine (GEM) course. Doctors with a background in primary care who were also involved in undergraduate teaching rated how necessary they considered a number of knowledge, skills and attitudes items were for inclusion in the CAP curriculum.

Methods

An online questionnaire study was carried out using modified Delphi methodology in two rounds. The questionnaire was derived from a list of CAP learning objectives and/or curricular content obtained from a thorough review of the literature. 23 of the 24 doctors who had agreed to participate went on to complete the round one questionnaire (95.8% response rate) with 19 also completing round 2 (82.6%). Where there was high agreement (70% or more) amongst participants, items were considered as having sufficient consensus to either accept or reject them. Mean scores were then used as a way to prioritise items.

Results

At the end of round two, there was consensus to consider including 26 of the 34 knowledge items, 16 of the 20 skills items and three of the four attitudes items in the CAP curriculum. The most highly rated knowledge, skills and attitudes items were depression/ suicide; communicating with children, young people and families; and rapport building. The majority (83.3%) of round two responders, considered that the current amount of CAP teaching time was “too little”.

Conclusions

Delphi methodology proved useful for determining consensus and the priority rankings of the CAP knowledge, skills and attitudes items can now be used to help educators determine which topics to focus upon. The study findings support the need for additional CAP teaching time in the GEM curriculum and will help to shape new CAP content. Additional formal CAP teaching time has already been incorporated into the psychiatry speciality attachment, a new clinical skills session has been developed and CAP topics have been introduced into written and clinical examinations.