Afatinib use in non-small cell lung cancer previously sensitive to epidermal growth factor receptor inhibitors: the United Kingdom Named Patient Programme.

INTRODUCTION: Afatinib prolongs progression-free survival (PFS) in patients with non-small cell lung cancer (NSCLC) who were previously sensitive to erlotinib or gefitinib. This study investigated experience of afatinib under a Named Patient Use (NPU) programme. PATIENTS AND METHODS: Retrospective data for 63 patients were collected, including demographics, dose, toxicity and clinical efficacy. RESULTS: Response rate and median PFS were 14.3% and 2.6months, respectively. Diarrhoea and rash were the most common toxicities; 46% of patients required a dose reduction and 41% had a dose delay. CONCLUSIONS: Efficacy and safety in the NPU programme are consistent with the LUX-Lung 1 trial.

Inefficient cerebral recruitment as a vulnerability marker for schizophrenia.

BACKGROUND: Patients with schizophrenia and their first-degree relatives exhibit both abnormally diminished and increased neural activation during cognitive tasks. In particular, excessive task-related activity is often observed when tasks are easy, suggesting that inefficient cerebral recruitment may be a marker of vulnerability for schizophrenia. This hypothesis might best be tested using a very easy task, thus avoiding confounding by individual differences in task difficulty. METHOD: Eighteen people with schizophrenia, 18 unaffected full siblings of patients with schizophrenia and 26 healthy controls performed an easy auditory target-detection task in a 3-T magnetic resonance imaging (MRI) scanner. Groups were matched for accuracy on the task. Blood oxygen level-dependent (BOLD) responses to non-target stimuli in participants with vulnerability for schizophrenia (siblings and patients) were compared with those of healthy controls, and those of patients with those of unaffected siblings. BOLD responses to targets were compared with baseline, across groups. RESULTS: Subjects with vulnerability for schizophrenia showed significant hyperactivation to non-targets in brain areas activated by targets in all groups, in addition to reduced deactivation to non-targets in areas suppressed by targets in all groups. Siblings showed greater activation than patients to non-targets in the medial frontal cortex. Patients exhibited significantly longer reaction times (RTs) than unaffected siblings and healthy controls. CONCLUSIONS: Inefficient cerebral recruitment is a vulnerability marker for schizophrenia, marked by reduced suppression of brain areas normally deactivated in response to task stimuli, and increased activation of areas normally activated in response to task stimuli. Moreover, siblings show additional activation in the medial frontal cortex that may be protective.

Reduced event-related low frequency EEG activity in schizophrenia during an auditory oddball task.

This study examines EEG low frequency characteristics which have been linked to specific cognitive functions such as stimulus encoding and attention during an auditory oddball task in schizophrenia patients and healthy controls. EEG data was recorded from 17 young schizophrenia patients in a stable phase of their illness and 17 healthy controls performing an auditory oddball task. Evoked and induced delta and theta activity, N100, P300 amplitude were computed. Between 200-500 ms after a stimulus was presented, patients displayed significantly reduced P300, less evoked and induced delta and theta activity than controls. We conclude that the well known finding of P300 reduction in schizophrenia can be linked to reductions in delta and theta activity, which are a manifestation of impaired stimulus evaluation, memory retrieval, and a lack of sustained attention.

Cognitive deficits in early-onset schizophrenia spectrum patients and their non-psychotic siblings: a comparison with ADHD.

BACKGROUND: Previous research has shown cognitive deficits in patients with schizophrenia spectrum disorders in the areas of executive function, verbal memory and attention. Subtle deficits have been shown in healthy first-degree relatives of patients, suggesting that they may be trait markers. The specificity of these markers for schizophrenia compared with another neurodevelopmental disorder, Attention Deficit Hyperactivity Disorder (ADHD) has not been reliably established. METHODS: The Rey Auditory Verbal Learning Test (RAVLT), Hayling Sentence Completion Test (HSCT), FAS Test of orthographic verbal fluency (FAS) and Continuous Performance Test-Identical Pairs (CPT-IP) were administered to adolescent schizophrenia spectrum patients (SZ; n=30), adolescent siblings of schizophrenia spectrum patients (SZ-SIB; n=36), healthy control participants (HC; n=72); a neurodevelopmental comparison group of adolescents with ADHD (n=27). RESULTS: The SZ group were impaired on all measures. The SZ-SIB group were impaired on IQ, immediate recall (RAVLT), target sensitivity (CPT-IP), response initiation (HSCT); error rates for the FAS and HSCT. There were no significant differences between the SZ-SIB and ADHD groups on individual measures of cognitive function. Principal Components Analysis revealed four factors on which further analyses were conducted. The SZ-SIB and ADHD groups showed different profiles of impairment on components related to response initiation and sustained attention/vigilance when each was compared with the HC group. CONCLUSIONS: Deficits in intellectual function, verbal memory and response initiation/inhibition were found in the SZ-SIB group indicating that these are markers of risk for schizophrenia. Subtle differences in profiles of impairment in the SZ-SIB and ADHD groups on composite measures of attention and response initiation require further investigation.

A computed tomography-based protocol vs conventional clinical mark-up for breast electron boost.

AIMS: Computed tomography planning of whole breast radiotherapy (WBRT) improves breast coverage and reduces the normal tissue dose. Computed tomography planning may increase tumour bed boost treatment accuracy. The aims of this investigation were (1) to compare the breast boost volume treated with clinical mark-up with the volume delineated with computed tomography planning and (2) to study tumour bed volume changes between the initial planning computed tomography scan and a second computed tomography scan at the time of breast boost mark-up. MATERIALS AND METHODS: Women receiving adjuvant WBRT and an electron boost after breast-conserving surgery were eligible. As per standard practice, WBRT was computed tomography planned while the boost electron portal was clinically defined. Electron field borders were then traced with wire and a second computed tomography scan was carried out in the boost treatment position. Post-surgical radiological abnormalities were contoured to create a tumour bed clinical target volume (CTV) on both scans (CTV1 and CTV2). A 1cm margin to CTV2 defined the planning target volume (PTV). The proportions of the CTV2 and PTV receiving 90% (V90) and 80% (V80) of the dose were calculated. Changes in volume between CTV1 and CTV2 were analysed. RESULTS: Data from 47 eligible patients were analysed. The mean V90 for the PTV was 61%. Lower electron energy (P<0.001) and small field sizes (P=0.004) were associated with a low V90. The mean CTV decreased by 4.3 cm3 (P=0.014) and was smaller in those with a long surgery to computed tomography interval (P=0.008). On average, the 90% isodose covered 61 cm3 of normal tissue. CONCLUSIONS: Conventional clinical breast boost planning is inaccurate. Electron boost computed tomography planning together with appropriate surgical clip placement and the use of mammograms and pathological information should provide optimal coverage of the tumour site. The boost could usually be planned from the initial computed tomography scan.

Cuffed endotracheal tube use in paediatric prehospital intubation: challenging the doctrine?

Questioning traditional doctrines is essential if patient care is to improve and progress. Historically accepted teaching is to use uncuffed tubes in all children up to puberty. This has been the practice in anaesthesia, intensive care and paediatric resuscitation both in and out of hospital. The use of cuffed endotracheal tubes (ETTs) in pre-pubertal children is evolving in general anaesthesia and intensive care in hospital practice. In contrast, uncuffed tubes are still widely recommended for use in the prehospital environment in this age group. There are a number of good reasons why a cuffed tube should be considered in preference to an uncuffed tube in children intubated out of hospital, regardless of their age or size. There are also some counterarguments which are worthy of consideration. This article presents the arguments for and against the use of cuffed tubes in children in prehospital care with a view to stimulating open discussion and debate.

A comparison of the effects of IGF-I and insulin on glucose metabolism, fat metabolism and the cardiovascular system in normal human volunteers.

The metabolic and cardiovascular effects of recombinant human IGF-I were compared to insulin in six normal subjects. Subjects were studied twice and intravenously received an infusion of [6,6-2H2]glucose (0-480 min) and in random order either IGF-I 20 micrograms kg-1 h-1 (43.7 pmol kg-1 min-1 or insulin 0.5 mU kg-1 min-1 (3.4 pmol kg-1 min-1) with an euglycaemic clamp. One subject was withdrawn following a serious adverse event. During the IGF-I infusion glucose appearance rate (Ra) decreased from 1.79 +/- 0.13 at baseline (150-180 min) to 0.35 +/- 0.26 mg kg-1 min-1 (P < 0.01) at 360 min, and glucose utilization rate (Rd) increased from 1.79 +/- 0.28 to 4.17 +/- 0.84 mg kg-1 min-1 (P < 0.01). There was no change in free fatty acids (FFA) and an increase (percentage change from pre-infusion mean) in cardiac output +l37.3% +/- 9% (P < 0.01), heart rate +13% +/- 2% (P < 0.01) and stroke volume +21% +/- 7% (P < 0.05). During the insulin infusion glucose Ra decreased from 1.89 +/- 0.13 to 0.34 +/- 0.33 mg kg-1 min-1 (P < 0.01) and FFA from 0.546 mmol l-1 to 0.198 mmol l-1 (P < 0.01), glucose Rd increased from 1.89 +/- 0.18 to 5.41 +/- 1.47 mg kg-1 min-1 (P < 0.01) and there were no significant changes in the cardiovascular variables.

Pholedrine: a substitute for hydroxyamphetamine as a diagnostic eyedrop test in Horner's syndrome.

Mydriatic responses to eyedrops containing the indirect acting sympathomimetic amines tyramine, hydroxyamphetamine, and pholedrine have been compared in 10 healthy subjects. Pholedrine, the n-methyl derivative of hydroxyamphetamine, at a concentration of 1% had effects similar to those produced by 0.5% hydroxyamphetamine itself. Pretreatment with topical guanethidine attenuated its responses and in 13 patients with unilateral Horner's syndrome it distinguished clearly those five patients who had preganglionic from the eight with postganglionic lesions. It is concluded that 1% pholedrine may be substituted for 0.5% hydroxyamphetamine, which is no longer available, as a diagnostic agent for use in Horner's syndrome.

Delay in the diagnosis of breast cancer: the effect of the introduction of fine needle aspiration cytology to a breast clinic.

Fine needle aspiration cytology (FNAC) was introduced to a District General Hospital Breast Clinic in 1984 and since that time the rate of surgical excision biopsy for benign breast disease has halved. The rate of benign to malignant breast operations fell from 2.0 to 0.7 over a 7-year period from 1982 to 1988. During this period the diagnosis of breast cancer was made at the first clinic appointment in 85% of women. However, a delay in diagnosis of more than 50 days occurred in 33 patients (6.9%) and there was little difference in the annual rate of delayed diagnosis despite the addition of FNAC as an extra diagnostic tool in the later years of the study. Eighty-five per cent of patients with a delayed diagnosis were under the age of 55 (mean and median age 47) years. FNAC is a useful adjunct in the management of patients with diagnostic breast problems, but even in combination with mammography is not always sufficiently sensitive to exclude malignancy, particularly in young women.