G J Gibson

Epidermal growth factor receptors in non-small cell lung cancer

The epidermal growth factor receptor is homologous to the oncogene erb-beta and is the receptor for a class of tumour growth factors (TGF-alpha). The clinical correlations with its expression were studied in 77 non-small cell lung cancers (NSCLC). They were stained for epidermal growth factor receptor (EGFr) by means of an indirect immunoperoxidase technique using a monoclonal antibody against the receptor. Normal lung tissue and normal bronchus were stained for comparison. Cancer tissue showed significantly increased staining compared to normal lung (P less than 0.05). Staining for EGFr in 40 squamous carcinomas was significantly stronger than in 37 specimens of other types of NSCLC (P less than 0.05), and staining in stage three NSCLC was stronger than in stage 1 and 2 (P less than 0.05). These results suggest that the presence of a high intensity of staining for EGF receptor is associated with spread of human non-small cell lung cancer and this receptor may be a suitable target for therapy.

Noninvasive ventilation in ALS Indications and effect on quality of life

Background: Noninvasive ventilation (NIV) probably improves survival in ALS, but the magnitude and duration of any improvement in quality of life (QoL) and the optimal criteria for initiating treatment are unclear. Methods: QoL (Short Form-36 [SF-36], Chronic Respiratory Disease Questionnaire, Sleep Apnea Quality of Life Index) and respiratory function were assessed every 2 months and polysomnography every 4 months in 22 subjects with ALS. A trial of NIV was offered when subjects met one or more predefined criteria: orthopnea, daytime sleepiness, unrefreshing sleep, daytime hypercapnia, nocturnal desaturation, or an apnea–hypopnea index (AHI) of >10. Seventeen subjects were offered a trial of NIV; 15 accepted, and 10 continued treatment subsequently. Outcome was assessed by changes in QoL and NIV compliance (h/day). Subjects were followed to death or for at least 26 months. Results: QoL domains assessing sleep-related problems and mental health improved (effect sizes 0.88 to 1.77, p < 0.05) and were maintained for 252 to 458 days. Median survival following successful initiation of NIV was 512 days, and survival and duration of QoL benefit were strongly related to NIV compliance. Vital capacity declined more slowly following initiation of NIV. Orthopnea was the best predictor of benefit from, and compliance with, NIV. Daytime hypercapnia and nocturnal desaturation also predicted benefit but were less sensitive. Sleep-related symptoms were less specific, and AHI > 10 was unhelpful. Moderate or severe bulbar weakness was associated with lower compliance and less improvement in QoL. Conclusions: NIV use was associated with improved QoL and survival. Subjects with orthopnea and preserved bulbar function showed the largest benefit.

The relationship of quantitative epidermal growth factor receptor expression in non-small cell lung cancer to long term survival

Increased expression of epidermal growth factor receptor (EGFr) has been reported in non small cell lung cancers (NSCLC) when compared to normal lung. We have examined post-operative survival in 19 surgically treated patients with NSCLC who had full characterisation of EGFr on primary tumour membrane preparations from resection specimens. There were ten squamous, seven adeno and two large cell carcinomas. The median concentration of high affinity sites was 31 fmol per mg of protein (4-1532) and the median dissociation constant (Kd) of these high affinity sites was 2.3 x 10(-10) per mol (1.2-30 x 10(-10)). Seven patients survived over 5 years. Twelve patients died between 8.5 and 55 months from the time of surgery. When > 5 year survivors were compared to non-survivors there was no difference as regards tumour size or stage, or as regards age or sex. The survivors had a median concentration of high affinity EGFr sites of 16.1 fmol mg-1 protein compared to a median concentration of 68.6 fmol mg-1 protein in the non-survivors (P = 0.01 Wilcoxon test). No long term survivor had > 35 fmol mg-1 protein of receptor. Thus EGFr quantitation may give independent prognostic information in NSCLC and help to select patients for adjuvant therapy after surgery. These results need confirmation in a larger prospective study.

Sleep and Breathing in Neuromuscular Disease

Respiratory muscle weakness in neuromuscular disease causes significant morbidity and mortality. The published data on respiratory muscle activity and breathing during sleep in normal subjects, the impact of respiratory muscle weakness on sleep and breathing and the relations to daytime respiratory function in neuromuscular disease are reviewed here. In normal subjects during sleep upper airway resistance increases, chemosensitivity is reduced and the wakefulness drive to breathe is lost, resulting in a fall in ventilation. During rapid eye movement (REM) sleep, ribcage and accessory breathing muscles are suppressed, particularly during bursts of eye movements, and breathing is more irregular, rapid and shallow, with a further fall in ventilation. In subjects with respiratory muscle weakness sleep is fragmented, with shorter total sleep time, frequent arousals, an increase in stage 1 sleep and a reduction in, or complete suppression of, REM sleep. Sleepdisordered breathing and nocturnal desaturation are common and most severe during REM sleep. Correlations between daytime respiratory function and nocturnal desaturation are moderate or weak, but daytime respiratory function has greater prognostic value than nocturnal measurements. Noninvasive ventilation improves sleep quality and breathing in subjects with respiratory muscle weakness. However, the optimal criteria for initiation of ventilation and its role in rapidly progressive neuromuscular diseases are unclear.

Obesity, respiratory function and breathlessness

Oxygen consumption dedicated to respiratory work (V̇O2RESP) during quiet breathing is small in normal patients. In the morbidly obese, at high minute ventilations, V̇O2RESP is greater than in normal patients, but V̇O2RESP during quiet breathing in these patients is not known. We postulated that such patients have increased V̇O2RESP at rest which may predispose them to respiratory failure when additional respiratory workloads are imposed. We measured baseline V̇O2 in morbidly obese patients immediately prior to gastric bypass surgery and again after intubation, mechanical ventilation, and paralysis, and compared their change in V̇O2 to nonobese patients scheduled for elective abdominal surgery. Baseline V̇O2 was higher in the obese patients compared with control patients (354.6 versus 221.4 ml/min; p= 0.0001) and the change in V̇O2 from spontaneous breathing to mechanical ventilation was significant in the obese patients (354.6 versus 297.2 ml/min; p=0.0002) but not the control patients (221.4 versus 219.8 ml/min; p=0.86). We conclude that morbidly obese patients dedicate a disproportionately high percentage of total V̇O2 to conduct respiratory work, even during quiet breathing. This relative inefficiency suggests a decreased ventilatory reserve and a predisposition to respiratory failure in the setting of even mild pulmonary or systemic insults. (Am J Respir Crit Care Med 1999;160:883–6)

Respiratory function vs sleep-disordered breathing as predictors of QOL in ALS

Background: Most patients with ALS have evidence of respiratory muscle weakness at diagnosis, and death is usually due to respiratory failure. Sleep disruption, possibly due to apneas, hypopneas, orthopnea, or REM-related desaturation, is common. The relative impact of these factors on quality of life has not been established. Methods: The authors recruited 23 subjects with probable or definite ALS. Quality of life was assessed using generic and specific instruments, and respiratory muscle strength by measurement of vital capacity, maximum static pressures, and sniff nasal inspiratory pressure. Twenty-two subjects underwent polysomnography. Overall limb and axial muscle strength was estimated using a summated muscle score based on the Medical Research Council clinical scale. Results: On univariate analysis, there were moderate to strong correlations between quality of life and all measurements of respiratory muscle function (R = 0.42–0.82). The correlations with selected polysomnographic indices were weaker and less consistent (R = 0.44–0.59). Multivariate analysis showed that maximum static inspiratory pressure was the strongest independent predictor of quality of life. Conclusion: Quality of life was strongly and independently related to respiratory muscle function. Relations with polysomnographic indices were weaker and were attributable to respiratory muscle weakness. Respiratory muscle weakness is much more important than the frequency of apneas and hypopneas in determining quality of life in ALS.

Depression and anxiety related subtypes in Parkinson's disease

Background Depression and anxiety are common in Parkinsons disease (PD) and although clinically important remain poorly understood and managed. To date, research has tended to treat depression and anxiety as distinct phenomena. There is growing evidence for heterogeneity in PD in the motor and cognitive domains, with implications for pathophysiology and outcome. Similar heterogeneity may exist in the domain of depression and anxiety. Objective To identify the main anxiety and depression related subtype(s) in PD and their associated demographic and clinical features. Methods A sample of 513 patients with PD received a detailed assessment of depression and anxiety related symptomatology. Latent Class Analysis (LCA) was used to identify putative depression and anxiety related subtypes. Results LCA identified four classes, two interpretable as ‘anxiety related’: one anxiety alone (22.0%) and the other anxiety coexisting with prominent depressive symptoms (8.6%). A third subtype (9%) showed a prominent depressive profile only without significant anxiety. The final class (60.4%) showed a low probability of prominent affective symptoms. The validity of the four classes was supported by distinct patterns of association with important demographic and clinical variables. Conclusion Depression in PD may manifest in two clinical phenotypes, one ‘anxious–depressed’ and the other ‘depressed’. However, a further large proportion of patients can have relatively isolated anxiety. Further study of these putative phenotypes may identify important differences in pathophysiology and other aetiologically important factors and focus research on developing more targeted and effective treatment.

Predicting outcomes following hospitalization for acute exacerbations of COPD.

Acute exacerbations of chronic obstructive pulmonary disease (AECOPD) are a frequent cause of hospital admission and are associated with significant morbidity, mortality, high readmission rates and high resource utilization. More accurate prediction of survival and readmission in patients hospitalized with AECOPD should help to optimize clinical management and allocation of resources, including targeting of palliative care and strategies to reduce readmissions. We have reviewed the published retrospective and prospective studies in this field to identify the factors most likely to be of value in predicting in-hospital and post-discharge mortality, and readmission of patients hospitalized for AECOPD. The prognostic factors which appear most important vary with the particular outcome under consideration. In-hospital mortality is related most clearly to the patients acute physiological state and to the development of acute comorbidity, while post-discharge mortality particularly reflects the severity of the underlying COPD, as well as specific comorbidities, especially cardiac disease. Important factors influencing the frequency of readmission include functional limitation and poor health-related quality of life. Large prospective studies which incorporate all the potentially relevant variables are required to refine prediction of the important outcomes of AECOPD and thus to inform clinical decision making, for example on escalation of care, facilitated discharge and provision of palliative care.

Snoring, daytime sleepiness and stroke: a case–control study of first-ever stroke

Previous reports have shown an association between snoring and stroke but it is not clear whether this reflects confounding factors nor whether the association is attributable to obstructive sleep apnoea (OSA). We performed a case–control study of 181 patients admitted to hospital with first‐ever stroke and community control subjects matched individually for age, sex and general practitioner. Subjects were interviewed with a structured questionnaire to identify snoring, daytime sleepiness and stroke risk factors. The association between snoring alone and stroke was not statistically significant: odds ratio (95% CI) 1.44 (0.88, 2.41). Daytime sleepiness was, however, significantly associated with stroke: odds ratio 3.07 (1.65, 6.08). Multiple logistic regression showed that hypertension, current smoking, taking alcohol regularly (negatively) and a higher Epworth sleepiness score were independently associated with stroke. The results suggest that the previously reported association between ‘simple’ snoring and stroke might have been due to poor controlling for confounding variables. Our study suggests an association with greater sleepiness prestroke, the cause of which is unclear, although OSA is a possible candidate.

Music and the wellbeing of people with dementia

While therapeutic interventions involving music have been shown to have benefits for people with dementia, little research has examined the role of music and music-related activities in their everyday lives. This paper presents the results of qualitative research that explored this role in terms of: the meaning and importance of music in everyday life; the benefits derived from participation in music-related activities; and the problems of engaging with music. Data were collected during in-depth interviews with 26 people with dementia and their carers, who lived either in their own homes or in residential care in different parts of England. The paper illustrates the many different ways in which people with dementia experience music. As well as being enjoyed in its own right, music can enable people to participate in activities that are enjoyable and personally meaningful. It is an important source of social cohesion and social contact, supports participation in various activities within and outside the household, and provides a degree of empowerment and control over their everyday situations. The practical implications for the provision of care and support for people with dementia are discussed. The scope and implications for technological development to promote access to music are also discussed.