Nadia Yousaf

Long-term low-dose erythromycin in patients with unexplained chronic cough: a double-blind placebo controlled trial

Aims Unexplained chronic cough is a common condition with no satisfactory treatments. Previous work has suggested that cough may be linked to neutrophilic airway inflammation. This study tested the hypothesis that long-term low-dose erythromycin reduces the induced sputum neutrophil count and 24 h cough frequency in patients with unexplained chronic cough. Methods 30 patients with an unexplained chronic cough lasting more than 8 weeks were randomly assigned to take 250 mg erythromycin once daily (n=15) or placebo (n=15) for 12 weeks in a double-blind parallel group study. Cough frequency, cough reflex sensitivity and cough severity were assessed at baseline, 6, 12 and 24 weeks. The primary outcome measure was change in 24 h cough frequency at 12 weeks. Results There was no difference in the change in cough frequency between the erythromycin and placebo groups at 12 weeks (mean difference in fold change 1.1; 95% CI 0.7 to 1.5; p=0.585) or at other times. There was a statistically significant between-treatment difference in the change in sputum neutrophils at 12 weeks (−10.2% vs +6.6% with erythromycin and placebo; mean difference 16.8%; 95% CI 1.6 to 32.1; p=0.03) but not at other times. There was no difference in the change in other measures of cough between treatments. Conclusions Treatment with low-dose erythromycin for 12 weeks reduces the induced sputum neutrophil count but not cough frequency or severity in patients with unexplained chronic cough.

Cough frequency in health and disease

To the Editor: Chronic cough is a difficult clinical problem, partly because there is an absence of well-validated means to assess cough [1, 2]. We have previously reported that the semi-automated computerised Leicester Cough Monitor detects cough accurately over 6 h and that cough frequency is increased in patients with chronic cough compared to controls [3, 4]. There remains uncertainty on the performance of the system over 24 h and across the range of expected cough frequency in larger populations. We set out to address these questions in healthy adult volunteers and adult volunteers with respiratory disease. 44 healthy volunteers were recruited from those responding to a poster advertisement. All reported no current respiratory symptoms, were nonsmokers with a <5 pack-yr past smoking history and had normal spirometric values, methacholine airway responsiveness and induced sputum inflammatory cell counts. 78 patients with respiratory disease were recruited from respiratory clinics. The diagnostic criteria for the conditions have been described previously [5]. Six current smokers and four males taking angiotensin converting enzyme inhibitors (ACEi) were also recruited. The study was approved by the Leicestershire, Northampton and Rutland Research Ethics Committee. All volunteers underwent spirometry and those with normal spirometry had a methacholine inhalation test using the tidal breathing method. The Leicester Cough Monitor (iRiver iFP-799 mp3 device; iRiver Europe GmbH, Eschborn, Germany and Sennheiser MKE 2–5 field microphone; Sennheiser electronic GmbH & Co. KG, Wedemark, Germany) was attached and recordings obtained and analysed as …

Melanoma epidemiology, biology and prognosis

Melanoma is a cancer arising from the malignant transformation of melanocytes. These pigment-producing cells derive embryologically from pluripotent neural crest stem cells. During foetal development they not only predominantly migrate to and differentiate within the epidermis, but also to other extra-cutaneous pigment-containing sites such as the eyes, meninges, oesophagus and mucous membranes. Three subtypes of melanoma can therefore be characterised: cutaneous melanoma (the most common) arising from melanocytes in the epidermis, mucosal melanoma from melanocytes residing in the mucous membranes and uveal melanoma from melanocytes residing in the ocular stroma. In this chapter we will consider each of these melanoma subtypes in turn, highlighting the differences in epidemiology, biology and prognosis between them.

The cost of ipilimumab toxicity: a single-centre analysis

There are no published data on the costs associated with investigating and managing toxicity from ipilimumab treatment in patients with metastatic melanoma. Patients treated with ipilimumab at The Royal Marsden Hospital between 1 September 2010 and 1 April 2013 were identified. Data on demographics, investigations and survival outcomes were collected. Patients with grade 3 or higher immune-related adverse events were identified, and costs of investigating and managing toxicities in them were calculated on the basis of standard National Health Service tariffs. Out of the 110 patients, 29 experienced grade 3/4 immune-related adverse events. The total cost of investigating and managing these patients was £140 680, or a median cost of £2860 per patient. Patients experiencing grade 3/4 toxicities had 1-, 2- and 3-year survival rates of 79, 59 and 46%, compared with 24, 17 and 15% in the group that did not experience significant toxicity (P<0.0005). The most common treatment-related toxicity identified was colitis. Two patients died from complications associated with ipilimumab colitis. The cost of ipilimumab toxicity is marginal in comparison with the total treatment cost. Patients treated with ipilimumab who develop significant toxicity have a higher than expected 1-, 2- and 3-year survival.

Phase I/II RAF kinase inhibitors in cancer therapy

Introduction: Aberrant activation of RAF signalling is a frequent finding in human cancers. BRAF is the only RAF family member that is commonly mutated, whilst CRAF and ARAF play important roles in the signal transduction from mutant RAS. BRAF-specific inhibitors have been more effective in the treatment of BRAF-mutant melanoma than BRAF-mutant thyroid and colorectal cancers. Areas covered: The review summarises the experience with RAF kinase inhibitors, including efficacy, modes of acquired resistance, and the mechanism behind the progression of pre-malignant RAS-mutant lesions observed with RAF kinase inhibitors. The authors review all the completed and ongoing Phase I or II clinical trials of RAF kinase inhibitors and discuss in detail the rationale behind the combinatorial approaches. Expert opinion: The success of RAF kinase inhibitors has demonstrated the necessity of genotype-driven treatment selection for cancer patients. The spectrum of responses in different tumour types is explained by feedback events that are determined by cell lineage. Dissection of these events and the mechanisms of acquired resistance will determine the appropriate combination therapies. Ongoing characterisation of RAS-MAPK regulation in malignant cells may aid the development of novel agents that have greater potency for the inhibition of activated RAF kinase, and lesser propensity for promotion of RAS-mutant tumours.

Predictors of objective cough frequency in pulmonary sarcoidosis

Cough is a common symptom of pulmonary sarcoidosis. This study aimed to quantify cough frequency, and investigate its relationship with cough reflex sensitivity, pulmonary function and health status. 32 patients with pulmonary sarcoidosis were compared with 40 healthy controls. Cough reflex sensitivity to capsaicin, objective 24-h cough counts, cough-specific health status, cough severity and cough triggers were measured. The predictors of cough frequency in sarcoidosis were determined in a multivariate analysis. Objective cough frequency was significantly raised in patients with sarcoidosis compared with healthy controls (p<0.001) and patients with cough had an impaired health status. Patients with pulmonary sarcoidosis had a heightened cough reflex sensitivity compared with healthy controls (p<0.001). Only cough reflex sensitivity was significantly associated with objective cough frequency in multivariate analysis, explaining 42% of the variance (p<0.001). There was no association between cough frequency, lung function, number of organs involved, chest radiograph stage or serum angiotensin-converting enzyme levels. Cough is a common and significant symptom in patients with sarcoidosis. Ambulatory objective cough monitoring provides novel insights into the determinants of cough in sarcoidosis, suggesting that cough reflex sensitivity may be more important than lung function and other measures of disease severity, and this should be investigated further. Cough reflex hypersensitivity is an important determinant of objective cough frequency in sarcoidosis http://ow.ly/W4q9e

Immune checkpoint inhibitors and cardiovascular toxicity

Immune checkpoint inhibitors are a new class of anticancer therapies that amplify T-cell-mediated immune responses against cancer cells. Immune checkpoint inhibitors have shown important benefits in phase 3 trials, and several agents have been approved for specific malignancies. Although adverse events from immune checkpoint inhibitors are a common occurrence, cardiotoxic effects are uncommon, but are often serious complications with a relatively high mortality. Most cardiotoxic effects appear to be inflammatory in nature. Clinical assessment of a combination of biomarkers, electrocardiography, cardiac imaging, and endomyocardial biopsy can be used to confirm a possible diagnosis. In this Review, we discuss the epidemiology of immune checkpoint inhibitor-mediated cardiotoxic effects, as well as their clinical presentation, subtypes, risk factors, pathophysiology, and clinical management, including the introduction of a new surveillance strategy.