Bradley R. Straatsma

Photocoagulation Treatment of Proliferative Diabetic Retinopathy: The Second Report of Diabetic Retinopathy Study Findings

Data from the Diabetic Retinopathy Study (DRS) show that photocoagulad inhibited the progression of retinopathy. These beneficial effects were noted to some degree in all those stages of diabetic retinopathy which were included in the Study. Some deleterious effects of treatment were also found, including losses of visual acuity and constriction of peripheral visual field. The risk of these harmful effects was considered acceptable in eyes with retinopathy in the moderate or severe retinopathy in the moderate or severe proliferative stage when the risk of severe visual loss without treatment was great. In early proliferative or severe nonproliferative retinopathy, when the risk of severe visual loss without treatment was less, the risks of harmful treatment effects assumed greater importance. In these earlier stages, DRS findings have not led to a clear choice between prompt treatment and deferral of treatment unless and until progression to a more severe stage occurs.

Dendritic Cell Vaccination Combined with CTLA4 Blockade in Patients with Metastatic Melanoma

Purpose: Tumor antigen–loaded dendritic cells (DC) are believed to activate antitumor immunity by stimulating T cells, and CTL-associated antigen 4 (CTLA4)–blocking antibodies should release a key negative regulatory pathway on T cells. The combination was tested in a phase I clinical trial in patients with advanced melanoma. Experimental Design: Autologous DC were pulsed with MART-126-35 peptide and administered with a dose escalation of the CTLA4-blocking antibody tremelimumab. Sixteen patients were accrued to five dose levels. Primary end points were safety and immune effects; clinical efficacy was a secondary end point. Results: Dose-limiting toxicities of grade 3 diarrhea and grade 2 hypophysitis developed in two of three patients receiving tremelimumab at 10 mg/kg monthly. Four patients had an objective tumor response, two partial responses and two complete responses, all melanoma free between 2 and 4 years after study initiation. There was no difference in immune monitoring results between patients with an objective tumor response and those without a response. Exploratory gene expression analysis suggested that immune-related gene signatures, in particular for B-cell function, may be important in predicting response. Conclusion: The combination of MART-1 peptide–pulsed DC and tremelimumab results in objective and durable tumor responses at the higher range of the expected response rate with either agent alone. (Clin Cancer Res 2009;15(19):6267–76)

Tissue Plasminogen Activator Treatment of Experimental Subretinal Hemorrhage

To determine if tissue plasminogen activator, a clot-specific fibrinolytic agent, could eventually be used to assist in the clearance or removal of subretinal hemorrhage, we studied the effect of subretinal injections of tissue plasminogen activator, autologous blood, balanced salt solution, and the combination of either tissue plasminogen activator or balanced salt solution after subretinal injection of autologous blood on retinal morphologic characteristics and clearance of subretinal hemorrhage in the albino rabbit. No morphologic evidence of tissue plasminogen activator toxicity was found in the rabbit retina at a dose of 25 to 50 μg/0.1 ml. Subretinal hemorrhage cleared faster after subretinal injection of tissue plasminogen activator when compared to balanced salt solution (P = .0005) but did not completely prevent overlying retinal degeneration. Both tissue plasminogen activator and balanced salt solution were found to decrease the toxic effects of subretinal blood on the morphologic characteristics of the rabbit retina, and this effect can be explained at least partly by dilution of the subretinal blood.

Enucleation Versus Plaque Irradiation for Choroidal Melanoma

The Collaborative Ocular Melanoma Study (COMS) is an international, multicenter-controlled study. The organization includes an Executive Committee, Steering Committee, 6 Central Units, 32 Clinical Centers, and a Data and Safety Monitoring Committee. Scientifically, the COMS consists of (1) a randomized trial of patients with medium choroidal melanoma treated with enucleation versus iodine-125 plaque irradiation, (2) a randomized trial of patients with large choroidal melanoma treated with enucleation versus preenucleation external beam irradiation and enucleation, and (3) a prospective observational study of patients with small choroidal melanoma to determine whether a randomized trial of treatment is appropriate. In design and conduct of the COMS, special consideration is given to biostatistics and sample size considerations, iodine-125 plaque irradiation of choroidal melanoma, and coordinated ocular melanoma research. Recruitment is in progress. However, the pool of eligible patients is limited and the COMS needs the continued support and cooperation of ophthalmologists throughout the United States and Canada.

Myelinated Retinal Nerve Fibers

In a series of 3,968 consecutive autopsies, myelinated nerve fibers of the retina were presented in 39 (0.98%) cases and bilateral in three (7.7%) affected cases; thus, 42 (0.54%) of the 7,936 eyes examined were affected. Myelinated nerve fiber lesions appeared as white or gray-white striated patches corresponding in shape to the distribution of retinal nerve fibers and demonstrated frayed borders. Myelinated retinal nerve fibers were continuous with the optic nerve head in 14 (33%) and discontinuous with the optic nerve head in 28 (66%) affected eyes. By light microscopy and electron microscopy, myelinated retinal fibers were marked by a ganglion cell axon surrounded by concentric lipoprotein lamellae that formed the myelin sheath. Glial cells were often prominent near the myelin sheaths, but other components of the sensory retina were morphologically normal. Clinically, 32 patients with myelinated retinal nerve fibers had comparable overall features, visual field defects less extensive than expected on the basis of ophthalmoscopic appearance, and normal findings on fluorescein angiography. Four patients had a syndrome characterized by ipsilateral extensive myelinated retinal nerve fibers, anisometropic myopia, amblyopia, and strabismus.

Apparent Disappearance of a Macular Hole Associated With Development of an Epiretinal Membrane

A macular hole in a 78-year-old man participating in a long-term follow-up study changed its biomicroscopic appearance dramatically as a result of changes in an epiretinal membrane. The macular hole became invisible and visual acuity improved from 20/70-2 to 20/30-2+2.

Detailed analysis of immunologic effects of the cytotoxic T lymphocyte-associated antigen 4-blocking monoclonal antibody tremelimumab in peripheral blood of patients with melanoma.

BackgroundCTLA4-blocking antibodies induce tumor regression in a subset of patients with melanoma. Analysis of immune parameters in peripheral blood may help define how responses are mediated.MethodsPeripheral blood from HLA-A*0201-positive patients with advanced melanoma receiving tremelimumab (formerly CP-675,206) at 10 mg/kg monthly was repeatedly sampled during the first 4 cycles. Samples were analyzed by 1) tetramer and ELISPOT assays for reactivity to CMV, EBV, MART1, gp100, and tyrosinase; 2) activation HLA-DR and memory CD45RO markers on CD4+/CD8+ cells; and 3) real-time quantitative PCR of mRNA for FoxP3 transcription factor, preferentially expressed by T regulatory cells. The primary endpoint was difference in MART1-specific T cells by tetramer assay. Immunological data were explored for significant trends using clustering analysis.ResultsThree of 12 patients eligible for immune monitoring had tumor regression lasting > 2 years without relapse. There was no significant change in percent of MART1-specific T cells by tetramer assay. Additionally, there was no generalized trend toward postdosing changes in other antigen-specific CD8+ cell populations, FoxP3 transcripts, or overall changes in surface expression of T-cell activation or memory markers. Unsupervised hierarchical clustering based on immune monitoring data segregated patients randomly. However, clustering according to T-cell activation or memory markers separated patients with clinical response and most patients with inflammatory toxicity into a common subgroup.ConclusionAdministration of CTLA4-blocking antibody tremelimumab to patients with advanced melanoma results in a subset of patients with long-lived tumor responses. T-cell activation and memory markers served as the only readout of the pharmacodynamic effects of this antibody in peripheral blood.Clinical trial registration numberNCT00086489

Diabetes Mellitus and Intraocular Lens Implantation

Prospective evaluation of extracapsular cataract extraction with posterior chamber intraocular lens (ECCE-posterior chamber IOL) in 234 eyes of 20 diabetics, with and without nonproliferative retinopathy, and 209 nondiabetics demonstrated no statistically significant difference in operative or postoperative complications. A postoperative final visual acuity of 20/40 or better was achieved in 65% of diabetic surgical eyes and in 90% of nondiabetic surgical eyes, a difference that was statistically significant (P = 0.0049). When eyes with diabetic retinopathy or other pre-existing ophthalmic disease responsible for decreased vision were excluded, postoperative visual acuity of 20/40 or better was obtained in 93% of diabetic eyes and 96% of nondiabetic eyes, a difference that was not statistically significant (P = 0.5045). Therefore, the relatively less favorable outcome of ECCE-posterior chamber IOL surgery in diabetics, with or without nonproliferative retinopathy, is due to greater frequency of retinopathy or other ophthalmic disease responsible for decreased vision. Based on this study and all available information, guidelines regarding diabetes mellitus and intraocular lens implantation are presented.

Myelinated Retinal Nerve Fibers Associated with Ipsilateral Myopia, Amblyopia, and Strabismus

Four patients had extensive unilateral myelinated nerve fibers associated with ipsilateral myopia, amblyopia, and strabismus. Their profound visual impairment, exotropia, and the early age onset of symptoms indicated that the amblyopia may have been organically caused. Prognosis is poor for even partial correction but good results have been obtained with intense therapy that includes full correction of the refractive error in each eye and extraocular muscle surgery if cosmetically necessary. In patients with axial myopia, images of a similar size will be produced by placing a lens of the correct power at the spectacle plane. In younger patients, a contact lens should not be used to correct the refractive error because it creates an undesirable anisometropia. Younger patients who have parafoveal fixation and no strabismus respond best to amblyopia therapy.

Posterior chamber intraocular lens implantation by ophthalmology residents. A prospective study of cataract surgery.

The UCLA Cataract Surgery Study Group evaluated extracapsular cataract extraction with posterior chamber intraocular lens implantation (ECCE-posterior chamber IOL) performed by eight senior ophthalmology residents with faculty supervision and five faculty ophthalmologists experienced in intraocular lens surgery. The first 18 consecutive ECCE-posterior chamber IOL operations performed by each resident and faculty surgeon after July 1, 1981, were analyzed. All 234 operations and follow-up conformed to a predetermined protocol. Resident surgery achieved 20/40 or better final visual acuity in 88% of eyes; faculty surgery achieved 20/40 or better in 89%. Excluding cases with macular degeneration or other pre-existing eye disease, resident surgery achieved 20/40 or better final visual acuity in 95% of eyes; faculty surgery achieved 20/40 or better in 96%. There was no statistically significant difference between the results of resident surgery and faculty surgery. With supervision, ophthalmology residents achieved results generally equivalent to results obtained by experienced ophthalmic surgeons.