Morton E. Smith

Collaborative Ocular Oncology Group report number 1: prospective validation of a multi-gene prognostic assay in uveal melanoma.

PURPOSE This study evaluates the prognostic performance of a 15 gene expression profiling (GEP) assay that assigns primary posterior uveal melanomas to prognostic subgroups: class 1 (low metastatic risk) and class 2 (high metastatic risk). DESIGN Prospective, multicenter study. PARTICIPANTS A total of 459 patients with posterior uveal melanoma were enrolled from 12 independent centers. TESTING Tumors were classified by GEP as class 1 or class 2. The first 260 samples were also analyzed for chromosome 3 status using a single nucleotide polymorphism assay. Net reclassification improvement analysis was performed to compare the prognostic accuracy of GEP with the 7th edition clinical Tumor-Node-Metastasis (TNM) classification and chromosome 3 status. MAIN OUTCOME MEASURES Patients were managed for their primary tumor and monitored for metastasis. RESULTS The GEP assay successfully classified 446 of 459 cases (97.2%). The GEP was class 1 in 276 cases (61.9%) and class 2 in 170 cases (38.1%). Median follow-up was 17.4 months (mean, 18.0 months). Metastasis was detected in 3 class 1 cases (1.1%) and 44 class 2 cases (25.9%) (log-rank test, P<10(-14)). Although there was an association between GEP class 2 and monosomy 3 (Fisher exact test, P<0.0001), 54 of 260 tumors (20.8%) were discordant for GEP and chromosome 3 status, among which GEP demonstrated superior prognostic accuracy (log-rank test, P = 0.0001). By using multivariate Cox modeling, GEP class had a stronger independent association with metastasis than any other prognostic factor (P<0.0001). Chromosome 3 status did not contribute additional prognostic information that was independent of GEP (P = 0.2). At 3 years follow-up, the net reclassification improvement of GEP over TNM classification was 0.43 (P = 0.001) and 0.38 (P = 0.004) over chromosome 3 status. CONCLUSIONS The GEP assay had a high technical success rate and was the most accurate prognostic marker among all of the factors analyzed. The GEP provided a highly significant improvement in prognostic accuracy over clinical TNM classification and chromosome 3 status. Chromosome 3 status did not provide prognostic information that was independent of GEP.

The natural history of retinopathy in insulin-dependent juvenile-onset diabetes

We determined the cross-sectional natural history of retinopathy by prospective study of 461 insulin-dependent juvenile-onset diabetics. In so doing, we compared the sensitivity of ophthalmoscopy, photography, and fluorescein angiography in detecting retinopathy. Photography was far more reliable than ophthalmoscopy in detecting early retinopathy and equivalent to angiography. Retinopathy was not present at diagnosis of diabetes. After a lag period, the prevalence of retinopathy rose in sigmoidal fashion, reaching 50% at just over seven years duration, and asymptotically approaching 90% at 17--50 years. Proliferative retinopathy was first seen at 13 years duration, and its prevalence rose to 26% at 26--50 years. From the natural history we computed the dimensions of a proposed clinical trial to test the effect of tight metabolic control in prevention of retinopathy.

Histologic Study of Eyes With Transsclerally Sutured Posterior Chamber Intraocular Lenses

We studied the postmortem histologic characteristics of two eyes that had undergone penetrating keratoplasty and transscleral suturing of a posterior chamber intraocular lens for bullous keratopathy. The eyes were studied three days postoperatively in a 79-year-old man with pseudophakia and six months postoperatively in an 83-year-old man with aphakia. We also removed a posterior chamber intraocular lens in a 73-year-old woman who had an epithelial downgrowth three months postoperatively. In the first two cases, only one of four haptics was successfully positioned in the sulcus. Histologic study disclosed a thin fibrous capsule surrounding the haptics at their attachment site, no inflammation around the transscleral portion of the suture, and exposure of a suture tip externally. In the third case, the intraocular lens fell back into the vitreous cavity after the fixation sutures were cut externally at the time of surgical removal. Stability of the lens in all three cases was primarily a result of intact transcleral sutures and not fibrous encapsulation or ciliary sulcus placement of haptics.

Reactivation of Latent Herpes Simplex Virus by Excimer Laser Photokeratectomy

We tested whether excimer laser photorefractive and phototherapeutic keratectomy may reactivate latent herpes simplex and cause recurrent keratitis in mice. Two of ten latently infected mice that were treated with ten excimer laser pulses to the corneal epithelium shed herpes simplex virus type 1, as did four of ten mice that were treated with 50 excimer laser pulses. Ocular shedding of herpes simplex virus was detected in four of ten mice that were treated with ethylenediamine-tetraacetic acid (EDTA) scraping of the corneal epithelium without laser keratectomy, and in six of ten mice on which combined EDTA-facilitated epithelial removal was performed followed by the application of ten excimer laser pulses. In both EDTA-treated groups, viral shedding was prolonged and 18 of 20 mice developed marked corneal opacification or neovascularization, or both. Corneal photoablation with the excimer laser may induce reactivation of latent herpes simplex virus, even in mice with clear and smooth-appearing corneas, and should be considered in the differential diagnosis of humans with persistent corneal epithelial defects after refractive or therapeutic excimer procedures.

Scanning Electron Microscopy of Intraocular Lenses

AT the meeting of the American Intra-Ocular Implant Society last year we presented our first results of the examination of intraocular lenses by scanning electron microscopy. Biodegradation of a Supramid loop tip surface was found in a lens removed because of ocular inflammation two years after surgery (Fig 1). Although superficial and certainly not unexpected, this demonstration was so dramatic that accounts of it were often exaggerated and some manufacturers added this to their reason for switching to the production of lenses with polypropylene loops. In a letter sent to the manufacturers, the superficiality and lack of clinical significance was emphasized. No eyes are known to have been damaged by the breaking of an irisclip lens loop and the only known case of loop tip failure was subsequently reported to us by Galin. The well-established record of safety of Supramid for iris-clip loops was noted and orderly caution was urged in the switch-over to polypropylene.

Radiation therapy for primary orbital lymphoma

PURPOSE The influence of tumor size, grade, thoroughness of staging workup, and radiation dose on disease control, radiation-related complications, and incidence of systemic progression of primary orbital lymphoma is analyzed. METHODS AND MATERIALS Twenty patients with Stage I primary orbital lymphoma were treated from August 1976 through August 1991 at Mallinckrodt Institute of Radiology. Staging workups included physical examination, chest x-ray, complete blood count (CBC), liver function test, and computerized tomography (CT) scan of the orbit, abdomen, and pelvis. Nineteen patients had bone marrow biopsy. The histological types based on the National Cancer Institute working formulation were 9 low-grade and 11 intermediate-grade, including five lymphocytic lymphomas of intermediate differentiation. The extension of disease and the volume of tumor were evaluated by CT scan of the orbit. The most commonly used radiation therapy technique was single anterior direct field with 4 MV or 6 MV photons. Lens was shielded or not treated in eight patients. Dose ranged from 20 to 43.2 Gy. Thirteen of 20 patients received 30 Gy. Minimum follow-up was 24 months (median, 4 years). RESULTS Local control was achieved in all 20 patients. One patient with lymphocytic lymphoma with intermediate differentiation developed disseminated disease. Actuarial disease-free survival (DFS) was 100% and 90% at 2 and 5 years, respectively. No retinopathy was observed. Cataracts were noted in seven patients at 1 to 10 years following irradiation (median, 2 years). Three patients developed lacrimal function disorder; however, no corneal ulceration occurred. CONCLUSIONS Thirty Gy in 15 fractions appears to be a sufficient dose for local control with acceptable morbidity, especially for low-grade, as well as certain types of intermediate-grade lymphomas, such as diffuse small cleaved cell and lymphocytic lymphoma of intermediate differentiation. Systemic dissemination is minimal, provided local control is achieved and initial staging workups are adequate.

Neoplastic angioendotheliomatosis: a variant of malignant lymphoma immunohistochemical and ultrastructural observations of three cases

Neoplastic angioendotheliomatosis (NAE) is a rare, fatal disease characterized by widespread intravascular proliferations of malignant cells of putative endothelial origin. Clinically, dermatologic and bizarre neurological manifestations predominate, but review of the reported cases of NAE reveals ophthalmic involvement to be frequent. To our knowledge, no reports of NAE have appeared in the ophthalmic literature. We describe three cases of NAE with the ocular manifestations of visual loss, cells in the vitreous, retinal artery occlusion, retinal vascular and pigment epithelial alterations, nystagmus, and cortical blindness. Autopsies (including eyes and central nervous system) revealed pancorporal involvement by intravascular anaplastic cells in each patient. In two patients massive extravascular involvement was also present. The tumor cells lacked ultrastructural features of endothelial cells and failed to stain for factor-VIII-related antigen. Common leukocyte antigen, a maker for hematopoietic cells, particularly lymphocytes, was detected on tumor cells in all cases, indicating that NAE is probably an extranodal lymphoma. The dramatic response of the central nervous system lesions to radiotherapy in one case supports this contention. It is suggested that this disorder be treated as a malignant lymphoma.

Triamcinolone-assisted internal limiting membrane peeling.

Purpose: To review our experience with triamcinolone-assisted pars plana vitrectomy for internal limiting membrane (ILM) peeling for various retinal diseases. Methods: Twenty-one patients underwent surgery in which intraoperative triamcinolone acetonide (TA) was used. Indications for surgery included epiretinal membrane (3 patients), branch retinal vein occlusion associated with macular edema (2), traction retinal detachment (3), diabetic macular edema (4), vitreous hemorrhage with diabetic macular edema (4), macular hole (4), and cystoid macular edema (1). Results: TA was useful in the removal of the ILM in all cases. There were no intraoperative complications or toxicity. The mean follow-up was 22 weeks (range, 9–30 weeks). Eleven patients improved by ≥2 Snellen lines, 1 lost ≥2 Snellen lines, and 9 were within 2 Snellen lines of preoperative vision at the last follow-up. Conclusions: The intraoperative use of TA improves visualization of ILMs associated with a variety of conditions. No intraoperative or postoperative complications were observed. TA-assisted removal of the ILM appears to be safe and cost effective. TA-assisted ILM peeling should be considered as an alternative to the use of intraoperative dyes.

Postoperative abnormalities of the choriocapillaris in exudative age-related macular degeneration.

AIMS: To study the incidence and possible cause of abnormalities of the subfoveal choriocapillaris after surgical excision of subfoveal choroidal neovascularisation in age-related macular degeneration (ARMD). METHODS: The postoperative fluorescein angiograms and colour photographs of 29 eyes of 29 patients were reviewed after surgical excision of subfoveal choroidal neovascularisation in exudative ARMD. Preoperative and postoperative fluorescein angiograms were examined for perfusion of the subfoveal choriocapillaris. The excised subfoveal choroidal neovascular membranes from eight eyes that demonstrated postoperative abnormalities of the choriocapillaris were embedded in paraffin, serially sectioned and examined for the presence of the choriocapillaris. RESULTS: Postoperative fluorescein angiograms revealed abnormal perfusion of the subfoveal choriocapillaris in 26 of the 29 eyes (90%) and in all eight eyes that had histopathological examination of the surgical specimens. Examination of serial sections demonstrated that none of the excised neovascular membranes contained choriocapillaris. CONCLUSIONS: Abnormal perfusion of the subfoveal choriocapillaris was frequently present following removal of the subfoveal neovascular membrane in ARMD. The histopathological study demonstrated that abnormalities of the choriocapillaris were not due to removal of the choriocapillaris at the time of surgery.

Fine Needle Aspiration Biopsy with Adjunct Immunohistochemistry in Intraocular Tumor Management

OBJECTIVE To assess the effectiveness of fine needle aspiration biopsy (FNAB), with and without immunohistochemistry (IHC), in the management of solid intraocular tumors. STUDY DESIGN Thirty-three consecutive adults undergoing FNAB of suspected intraocular tumors were studied. Clinical, cytologic and histologic diagnoses were correlated. The positive predictive value, sensitivity and specificity of FNAB for detecting malignancy, the effect of lHC on the final cytologic diagnosis and the number of patients in whom clinical management was altered as a result of cytologic evaluation were determined. RESULTS The positive predictive value was 96% with and 93% without adjunct IHC. The sensitivity and specificity of FNAB for detecting malignancy were 96% and 83%, respectively, with IHC. Without IHC, the sensitivity was unaltered, but the specificity was 67%. IHC confirmed the morphologic diagnosis in 75% of cases, made a diagnosis in 12.5% and changed a malignant diagnosis from carcinoma to melanoma in 6% of cases. The planned management was changed by the FNAB findings in 24% of patients. In 3 patients (9%), IHC was essential for diagnosis and management. No patients exhibited local tumor dissemination or recurrence associated with the biopsy. CONCLUSION FNAB is a safe, sensitive and specific method of establishing a tissue diagnosis in a subset of patients with solid intraocular tumors. The routine use of immunohistochemical stain ing increases the diagnostic utility of the technique and may change clinical management.