Fatal interstitial lung disease associated with high erlotinib and metabolite levels. A case report and a review of the literature.

INTRODUCTION: Erlotinib is an agent in the class of oral epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors. Although this class of agents is considered to be relatively safe, the most serious, but rare, adverse reaction is drug-associated interstitial lung disease (ILD). This potentially fatal adverse reaction has been often described with gefitinib, but has been less well described for erlotinib. We here describe a case report of fatal interstitial lung disease in a Caucasian man associated with erlotinib and high erlotinib and metabolite plasma levels and discuss it in the context of all documented cases of erlotinib associated ILD. METHODS: Our case was described and for the literature review a Pubmed and Google Scholar search was conducted for cases of erlotinib associated ILD. The retrieved publications were screened for relevant literature. RESULTS: Besides our case, a total of 19 cases of erlotinib-associated ILD were found. Eleven out 19 cases had a fatal outcome and in only one case erlotinib plasma concentrations were measured and found to be high. CONCLUSION: Erlotinib-associated ILD is a rare, serious and often fatal adverse reaction. Most likely, the cause for erlotinib-associated ILD is multifactorial and high drug levels may be present in patients without serious adverse reactions. However, considering the pharmacology of EGFR inhibitors, high drug and metabolite levels may play a role and future studies are warranted to identify risk factors and to investigate the role of elevated levels of erlotinib and its metabolites in the development of pulmonary toxicity.

[Haemoptysis as a complication of Behçet's disease]. / Hemoptoë als complicatie van de ziekte van behçet.

Three patients, two Moroccan men aged 27 and 25 and a Turkish man aged 25, presented with haemoptysis caused by pulmonary aneurysm. The aneurysms had formed as a complication of Behçet's disease. Two of them were treated with high doses of corticosteroids. One man recovered and another died as a consequence of massive haemoptysis. The third man underwent emergency thoracotomy and pneumectomy due to massive haemoptysis. Postoperatively he was treated with cyclosporine resulting in full recovery. Behçet's disease is a multisystem vasculitis characterised by orogenital ulcerations and uveitis. In a minority of cases pulmonary aneurysms develop, often causing massive haemoptysis. Aneurysms are often accompanied by venous thrombosis. Treatment consists of immunosuppressive therapy. Nevertheless a considerable number of patients die following massive haemoptysis.

Aortic root replacement with the pulmonary autograft: an invariably competent aortic valve?

BACKGROUND: Pulmonary autograft aortic root replacement was used in adults. Risk factors for aortic regurgitation (AR), and for pulmonary allograft valve stenosis are identified. METHODS: From February 1991 through April 1998, 80 adults (mean age 34.4 years) underwent pulmonary autograft aortic root replacement. Primary diagnosis was AR in 43 (53.7%) patients, aortic stenosis in 13 (16.3%) and mixed disease in 24 (30%) patients. A root reinforcement ring was used in 32 (40%) patients. RESULTS: There was no hospital mortality. Estimated patient survival is 100% at 7 years. A total of 3 patients underwent reoperation: 2 on the autograft for severe AR, 1 for pulmonary allograft stenosis. Freedom from reoperation on the autograft is 96.7 +/- 2.4% at 7 years. Multivariate analysis indicated bicuspid aortic valve disease as an incremental risk factor for AR at discharge (p = 0.036, odds 3.5). Univariate analysis identified operation for pure AR as risk factor for AR during follow-up (p = 0.041). Mild AR or more increased from 2.5% at discharge to 11.3% during follow-up (p = 0.008). Progression of AR was limited by the use of a reinforcement root ring (p = 0.031). Freedom from mild AR or more in patients with and without a reinforcement root ring was 100% and 72.9 +/- 9.3% respectively, at 5 years (p = 0.119). Pulmonary allograft stenosis occurred in 15 (22.5%) patients. Multivariate analysis revealed that large sized pulmonary allografts were less prone to stenosis (p = 0.048, odds 0.13). CONCLUSIONS: Pulmonary autograft root replacement can be performed with few complications. During follow-up, a significant increase in mild AR or more is observed. The use of a reinforcement root ring is effective in preventing progression of AR.

Macrophages and pancreatic islet amyloidosis.

Islet amyloid formed from islet amyloid polypeptide (IAPP, amylin) is found in spontaneously diabetic monkeys and cats. Islet amyloidosis is progressive, apparently irreversible and is associated with destruction of insulin-secreting cells. The role of macrophages in the destruction and removal of islet amyloid is unknown. Therefore, the presence and morphology of macrophages were determined by electron and quantitative light microscopy in islets of diabetic and nondiabetic man and monkeys and in transgenic mice expressing the gene for human IAPP. Tissue macrophages were present in all pancreatic sections and tissue distribution was similar in exocrine and endocrine areas. There was no difference in macrophage density in amyloidotic and amyloid-free islets in monkeys and man. Macrophage density was similar in islets of transgenic mice expressing human IAPP which do not contain amyloid in vivo but in which fibrils are formed in vitro following islet isolation compared to islets from mice expressing rat IAPP which is not amyloidogenic. IAPP amyloid fibrils were visible by electron microscopy in lysosomes of pancreatic macrophages in man, monkeys and human IAPP transgenic mice. Thus, human IAPP is internalised but inefficiently degraded by tissue macrophages. Diabetes-associated amyloidosis is not associated with visible recruitment of macrophages for removal of amyloid or islet debris.

Comparison of LysB28, ProB29-human insulin analog and regular human insulin in the correction of incidental hyperglycemia.

OBJECTIVE: To obtain clinically applicable data on the effects of regular human insulin and the LysB28,ProB29-human insulin analogue (lispro) on the correction of incidental hyperglycemia. RESEARCH DESIGN AND METHODS: The insulins were compared in a non-clamped randomized crossover study of 27 male IDDM patients. Hyperglycemia was induced by the withdrawal of the normal evening dose of insulin; the next morning patients fasted and received a single dose of study insulin according to a dosing nomogram. Blood glucose concentration and GR (a measure of glucose corrected for differences in administered insulin dose: GR = glucose concentration X BMI X insulin dose-1) were followed for 4 h. RESULTS: The time courses of blood glucose concentration and GR were significantly different after regular insulin in comparison with lispro (multiple analysis of variance, P < 0.001). At t = 120 min, glucose concentrations had decreased 1.4 mmol/l more with lispro than with regular insulin (95% confidence interval [CI] 0.6-2.3, P = 0.002). Similarly, GR had decreased 4.4 mol.kg.IU-1.m-5 more with lispro than with regular insulin (95% CI 2.6-6.2, P < 0.001). The overall difference in glucose values was 0.87 mmol/l (lispro < regular insulin, P = 0.036), and the overall difference in GR values was 1.96 mol.kg.IU-1.m-5 (lispro < regular insulin, P = NS). Unexpectedly, the intrinsic variability of GR was higher for lispro than for regular insulin. CONCLUSIONS: The more rapid action of lispro is an advantage in the correction of hyperglycemia, even though actual differences in glucose concentrations are smaller than suggested by previous clamped studies.