Philip I. Murray

ZD1839, a Selective Oral Epidermal Growth Factor Receptor–Tyrosine Kinase Inhibitor, Is Well Tolerated and Active in Patients With Solid, Malignant Tumors: Results of a Phase I Trial

PURPOSE To investigate the tolerability, pharmacokinetics, and antitumor activity of the oral, selective epidermal growth factor receptor-tyrosine kinase inhibitor ZD1839 in patients with solid malignant tumors. PATIENTS AND METHODS This was an open, phase I, escalating multiple-dose tolerability and pharmacokinetic trial. ZD1839 was administered once daily for 14 consecutive days followed by 14 days off treatment. Dose escalation started at 50 mg/d and continued to 925 mg or until consistent dose-limiting toxicity (DLT) was observed. RESULTS Sixty-four patients were entered at eight dose levels. The most frequent dose-related grade 1 and 2 adverse events were an acne-like (or folliculitis) rash, nausea, and diarrhea. Three of nine patients treated at 700 mg/d developed DLT (reversible grade 3 diarrhea); grade 3 and 4 events were uncommon. Exposure to ZD1839 was dose proportional, and the mean terminal half-life was 48 hours (range, 37 to 65). Four of 16 patients with non-small-cell lung cancer (NSCLC) had objective partial responses observed from ZD1839 300 to 700 mg/d. Overall, 16 patients remained on study for > or = 3 months, with seven of these patients (five with NSCLC, including three of the patients with partial response) remaining on study for > or = 6 months. CONCLUSION ZD1839 was well tolerated, with DLT observed at a dose well above that at which antitumor activity was seen. Pharmacokinetic analysis confirmed that ZD1839 was suitable for administration as a once-daily oral tablet formulation. Phase II monotherapy and phase III combination trials in NSCLC are being conducted to investigate further the efficacy, tolerability, and optimal daily dose of ZD1839.

Degree, duration, and causes of visual loss in uveitis

Background/aims: Uveitis is a major cause of visual morbidity in the working age group. The authors investigated the duration, degree, and causes of visual loss in uveitis patients with the aim of better defining the visual morbidity and identifying potential risk factors. Methods: A retrospective, non-interventional, observational survey of 315 consecutive patients attending a tertiary referral uveitis service. Results: The mean duration of follow up was 36.7 months. Reduced vision (⩽6/18) was found in 220/315 (69.95%) of the patients with a subset of 120 patients having vision ⩽6/60. Unilateral visual loss occurred in 109 (49.54%), while 111 (50.45%) had bilateral loss. The mean duration of visual loss was 21 months. Of the 148 patients with pan-uveitis, 125 (84.45%) had reduced vision, with 66 (53%) having vision ⩽6/60. Main causes of visual loss were cystoid macular oedema (CMO) (59/220, 26.8%), cataract (39/220, 17.7%), and combination of CMO and cataract (44/220, 20%). The following were predictive of a poorer visual prognosis: pan-uveitis (p = 0.0005), bilateral inflammation (p = 0.0005), increasing duration of reduced vision (p = 0.0005), an Indian or Pakistani ethnic background (p = 0.004), and increasing patient age (p = 0.02). Conclusion: Prolonged visual loss occurred in two thirds of uveitis patients, with 70 (22%) patients meeting the criteria for legal blindness at some point in their follow up. Older patients with bilateral inflammation and an increasing duration of reduced vision are at the greatest risk of severe visual loss (⩽6/60). CMO and cataract were responsible for visual loss in 64.5% of patients.

Behçet's disease: Ocular effects and treatment

Behçets disease (BD) is a systemic immune-mediated vasculitis of unclear origin. Major symptoms include oral aphthous ulcers, genital ulcerations, skin lesions, and ocular lesions. Eye involvement, which affects 60-80% of BD patients, is characterized by posterior or panuveitis with occlusive retinal vasculitis. The pathogenesis of BD remains unclear, but research of the last decades has shown a complex role of genetic factors (HLA-B51) predisposing to inflammation with involvement of the innate-immune system (neutrophils, NK cells), perpetuated by the adaptive immune response, most importantly T cells, against infectious- and/or auto-antigens. Despite aggressive immunosuppressive treatment, the visual prognosis of ocular BD was generally poor to date. Recently, novel biologic drugs, including interferon-alpha and tumour necrosis factor (TNF)-alpha-antagonists have been introduced in the treatment of ocular BD with very promising results and seem for the first time to improve the prognosis of the disease. This article will provide a current review of BD including recent developments in epidemiology, immunology, genetics, and treatment.

Understanding uveitis: the impact of research on visual outcomes.

The term uveitis encompasses a very diverse group of inflammatory ocular diseases that cause a significant burden of legal and economic blindness. Indeed, the socioeconomic impact of uveitis is at least as significant as that of diabetic retinopathy and, in the majority of cases, those affected are young individuals of working age. Significant progress has been made in our understanding of the mechanisms underlying the inflammatory process through the use of animal models, but correlation with human disease has proved elusive and many scientific approaches which appear highly effective in animal models prove to be less effective in patients. Nevertheless, effective, targeted treatments are needed in uveitis as current treatment is based on corticosteroids and immunosuppressive drugs whose usefulness is limited by their many side-effects. The aims of this review are to summarize the state of clinical research in uveitis, to identify gaps in our knowledge, and to propose new opportunities and methodologies for future developments in all aspects of uveitis research, including epidemiology, economic impact analysis, diagnosis, therapeutics, and clinical study design. Optimal patient management and efficient drug development depend on validated structured tools, such as those that have helped to drive a rapid acceleration in the means and methods available to assess and treat patients with rheumatoid arthritis and cancer. Uveitis care should witness a similar boom as the issues discussed are resolved.

A novel multilocus sequence typing scheme for the opportunistic pathogen Propionibacterium acnes and characterization of type I cell surface-associated antigens.

We have developed a novel multilocus sequence typing (MLST) scheme and database (http://pubmlst.org/pacnes/) for Propionibacterium acnes based on the analysis of seven core housekeeping genes. The scheme, which was validated against previously described antibody, single locus and random amplification of polymorphic DNA typing methods, displayed excellent resolution and differentiated 123 isolates into 37 sequence types (STs). An overall clonal population structure was detected with six eBURST groups representing the major clades I, II and III, along with two singletons. Two highly successful and global clonal lineages, ST6 (type IA) and ST10 (type IB(1)), representing 64 % of this current MLST isolate collection were identified. The ST6 clone and closely related single locus variants, which comprise a large clonal complex CC6, dominated isolates from patients with acne, and were also significantly associated with ophthalmic infections. Our data therefore support an association between acne and P. acnes strains from the type IA cluster and highlight the role of a widely disseminated clonal genotype in this condition. Characterization of type I cell surface-associated antigens that are not detected in ST10 or strains of type II and III identified two dermatan-sulphate-binding proteins with putative phase/antigenic variation signatures. We propose that the expression of these proteins by type IA organisms contributes to their role in the pathophysiology of acne and helps explain the recurrent nature of the disease. The MLST scheme and database described in this study should provide a valuable platform for future epidemiological and evolutionary studies of P. acnes.

International Uveitis Study Group (IUSG) Clinical Classification of Uveitis

A simplified clinical classification system of uveitis has been proposed by the International Uveitis Study Group. Its aim is to assist in the diagnosis and evaluation of patients with uveitis. Used in conjunction with other recognized classification systems it will also enable enrollment of patients for clinical trials, and contribute to clinical guidelines.

Ophthalmic manifestations of acute leukaemias: the ophthalmologist's role

AbstractWith evolving diagnostic and therapeutic advances, the survival of patients with acute leukaemia has considerably improved. This has led to an increase in the variability of ocular presentations in the form of side effects of the treatment and the ways leukaemic relapses are being first identified as an ocular presentation. Leukaemia may involve many ocular tissues either by direct infiltration, haemorrhage, ischaemia, or toxicity due to various chemotherapeutic agents. Ocular involvement may also be seen in graft-versus-host reaction in patients undergoing allogeneic bone marrow transplantation, or simply as increased susceptibility to infections as a result of immunosuppression that these patients undergo. This can range from simple bacterial conjunctivitis to an endophthalmitis. Leukaemia can present as pathology in the adnexae, conjunctiva, sclera, cornea, anterior chamber, iris, lens, vitreous, retina, choroid, and optic nerve. Recognition of the varied ocular presentations is also important in assessing the course and prognosis of leukaemia. We have presented a systematic approach taking each part of the eye in turn and outlining how leukaemia has been shown to affect it.

Inhibition of T Cell Apoptosis in the Aqueous Humor of Patients with Uveitis by IL-6/Soluble IL-6 Receptor trans-Signaling

A fundamental mechanism of immune privilege in the eye is the induction of T lymphocyte apoptosis. Intraocular inflammation in uveitis implies compromise of immune privilege. This study sought to determine whether apoptosis of T cells is actively inhibited in patients with uveitis and by what pathways this may occur. Apoptotic lymphocytes were found to be absent from aqueous humor (AqH) of virtually all patients with recent-onset uveitis. However, T cells removed from the eye were highly susceptible to both spontaneous and Fas ligand-induced apoptosis in vitro. AqH from patients with uveitis had no modulatory effect on Fas ligand-induced apoptosis, but strongly suppressed survival factor deprivation-induced apoptosis. In contrast, noninflammatory AqH from patients undergoing cataract surgery had no modulatory effects on apoptosis at all. These data suggest that triggering of the Fas pathway is diminished in uveitis, and also that homeostatic resolution through survival factor deprivation-induced apoptosis is inhibited by factors present in AqH. The most widely recognized pathways, common γ-chain cytokines and type I IFNs, did not contribute to AqH-mediated T cell survival. High levels of both IL-6 and soluble IL-6R were found in AqH. IL-6 alone did not induce T cell survival, because IL-6R expression on T cells in AqH was too low to facilitate signaling. However, combinations of IL-6 and soluble IL-6R were highly effective inhibitors of T cell apoptosis, suggesting that the trans-signaling pathway is likely to be a key mediator of T cell apoptosis inhibition mediated by uveitis AqH.

Fractal analysis of the normal human retinal fluorescein angiogram

The fractal dimension of the retinal vasculature and isolated venous and arterial trees down to a caliber of 40 microns was estimated in 23 routine fluorescein angiograms of normal retinas. Fractal dimension was determined with a method based on the box counting theorem. This method is less susceptible to the radial architecture of the retinal vascular tree than those previously reported (mass-radius relation and density-density correlation function). Two scale ranges with different fractal dimension were consistently present. The estimated fractal dimensions showed no significant difference between isolated arterial and venous trees which is not supported by previous reports. This method was designed for simple application in a clinical setting.

Evaluation of foldable intraocular lenses in patients with uveitis

OBJECTIVE To evaluate various foldable posterior chamber intraocular lenses (IOLs) after phacoemulsification in patients with uveitis. DESIGN A prospective, noncomparative, interventional case series. PARTICIPANTS Forty-nine consecutive patients (60 eyes) with various types of uveitis (anterior, n = 20; posterior, n = 1; panuveitis, n = 37, intermediate, n = 2). INTERVENTION All patients underwent phacoemulsification with foldable posterior chamber IOL implantation. All eyes were free of active inflammation at the time of surgery. A variety of IOL biomaterials were implanted: acrylic (n = 30), silicone (n = 17), and hydrogel (n = 13). MAIN OUTCOME MEASURES Detailed examination was performed by one masked observer. Several parameters were compared for each implant biomaterial, including level of best corrected Snellen visual acuity at final follow-up, presence of posterior synechiae, anterior capsular phimosis, posterior capsule opacification, and the degree of cellular deposits on the IOL optic. RESULTS There were 26 males and 23 females, aged 9 to 83 years (mean, 48 years). Follow-up ranged from 1 to 33 months (mean, 17.03 months). At final follow-up, 56 eyes (93.3%) had an improvement in visual acuity compared with preoperative levels as follows: 34 eyes (56.6%) achieved an improvement of four or more Snellen lines, and 44 eyes (73.3%) achieved 20/30 or better. Giant cells, observed on the IOL optic in 19 eyes (31.7%), were most often seen on the acrylic biomaterial at the 1-month follow-up, although this was not found to be statistically significant. Scratch marks produced by the lens-introducing forceps were seen in 24 eyes (40.0%), mainly on the acrylic and hydrogel optics. Posterior capsule opacification (PCO) occurred in 49 eyes (81.7%), with only 5 eyes requiring laser capsulotomy. There was no association between PCO and the various lens biomaterials. Other causes for reduced visual acuity included glaucomatous optic neuropathy (n = 5) and cystoid macular edema (n = 8). CONCLUSIONS The use of foldable IOLs in eyes with uveitis is safe, but the optimal biomaterial has yet to be found.