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Background Many CpGs become hyper or hypo-methylated with age. Multiple methods have been developed by Horvath et al. to estimate DNA methylation (DNAm) age including Pan-tissue, Skin & Blood, PhenoAge, and GrimAge. Pan-tissue and Skin & Blood try to estimate chronological age in the normal population whereas PhenoAge and GrimAge use surrogate markers associated with mortality to estimate biological age and its departure from chronological age. Here, we applied Horvath’s four methods to calculate and compare DNAm age in 499 subjects with type 1 diabetes (T1D) from the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study using DNAm data measured by Illumina EPIC array in the whole blood. Association of the four DNAm ages with development of diabetic complications including cardiovascular diseases (CVD), nephropathy, retinopathy, and neuropathy, and their risk factors were investigated. Results Pan-tissue and GrimAge were higher whereas Skin & Blood and PhenoAge were lower than chronological age (p < 0.0001). DNAm age was not associated with the risk of CVD or retinopathy over 18–20 years after DNAm measurement. However, higher PhenoAge (β = 0.023, p = 0.007) and GrimAge (β = 0.029, p = 0.002) were associated with higher albumin excretion rate (AER), an indicator of diabetic renal disease, measured over time. GrimAge was also associated with development of both diabetic peripheral neuropathy (OR = 1.07, p = 9.24E−3) and cardiovascular autonomic neuropathy (OR = 1.06, p = 0.011). Both HbA1c (β = 0.38, p = 0.026) and T1D duration (β = 0.01, p = 0.043) were associated with higher PhenoAge. Employment (β = − 1.99, p = 0.045) and leisure time (β = − 0.81, p = 0.022) physical activity were associated with lower Pan-tissue and Skin & Blood, respectively. BMI (β = 0.09, p = 0.048) and current smoking (β = 7.13, p = 9.03E−50) were positively associated with Skin & Blood and GrimAge, respectively. Blood pressure, lipid levels, pulse rate, and alcohol consumption were not associated with DNAm age regardless of the method used. Conclusions Various methods of measuring DNAm age are sub-optimal in detecting people at higher risk of developing diabetic complications although some work better than the others.

Background Preclinical studies suggest that imatinib resistance in gastrointestinal stromal tumor (GIST) can be mediated by MAP-kinase activation via fibroblast growth factor (FGF) signaling. In FGF stimulated GIST cell lines, BGJ398, a pan-FGFR kinase inhibitor in combination with imatinib, was cytotoxic and superior to imatinib therapy alone. In FGF-dependent GIST, the combination of BGJ398 and imatinib may provide a mechanism to overcome imatinib resistance. Methods This phase Ib study of BGJ398 and imatinib was performed in patients with imatinib refractory advanced GIST. A standard 3 + 3 dosing schema was utilized to determine the recommended phase II dose (RP2D). Two treatment schedules were evaluated incorporating imatinib 400 mg daily in combination with (A) BGJ398 daily 3 weeks on, 1 week off or (B) BGJ398 daily 1 week on, 3 weeks off. Results 16 patients enrolled. The median age was 54 years (range: 44-77), 81% were male, and the median number of lines of prior therapy was 4 [range: 2-6, 13 patients had ≥3 prior therapies]. 12 patients received treatment on schedule A [BGJ398 dose range: 25 - 75 mg]: 2 patients experienced dose limiting toxicities (DLT) (n = 1, myocardial infarction & grade (G)4 CPK elevation; n = 1, G3 ALT elevation) on schedule A (BGJ398 75 mg), significant hyperphosphatemia, an on-target effect, was not observed, implying the maximum tolerated dose was below the therapeutic dose. Following protocol amendment, 4 patients enrolled on schedule B [BGJ398 dose range: 75 - 100 mg]: no DLTs were observed. The most common treatment related adverse events occurring in >15% of patients included CPK elevation (50%), lipase elevation (44%), hyperphosphatemia (24%), anemia (19%), and peripheral edema (19%). Among the 12 evaluable patients, stable disease (SD) was the best response observed in 7 patients by RECIST v1.1 and 9 patients by CHOI. Stable disease ≥ 32 weeks was observed in 3 patients (25%). Median progression free survival was 12.1 weeks (95% CI 4.7-19.5 weeks). Conclusions Toxicity was encountered with the combination therapy of BGJ398 and imatinib. Due to withdrawal of sponsor support the study closed before the RP2D or dosing schedule of the combination therapy was identified. In heavily pre-treated patients, stable disease ≥ 32 weeks was observed in 3 of 12 evaluable patients. Trial Registration: NCT02257541 .

510 Background: FGFR3 alterations are prevalent in non-muscle-invasive bladder cancer (NMIBC). We conducted a marker lesion study of the oral FGFR inhibitor BGJ398 in patients with intermediate-risk NMIBC. Methods: Patients with recurrent clinical high-grade papillary NMIBC following intravesical BCG were eligible. FGFR3 alteration status was determined via testing of pre-treatment or archival tumor tissue. BGJ398 was administered at 125 mg PO daily for a 3 week on, 1 week off schedule (1 cycle). Response was determined after 2 cycles (at 7 weeks). Patients with a complete response (CR) had the option to continue therapy. Results: We enrolled four patients on trial, which we closed secondary to low accrual. Three patients had a CR at the 7-week evaluation. The other patient had a smaller, necrotic lesion after prematurely discontinuing treatment at 4 weeks. Clinically significant toxicities included eye disorders, skin and nail disorders, and elevations in LFTs. Two patients required dose reductions for toxicities. Two patients discontinued treatment before the 7-week evaluation, one for Grade 2 skin toxicity and the other for Grade 3 LFT elevation. All other toxicities were Grades 1 and 2. The other two patients continued treatment beyond a CR at 7 weeks but stopped after 3 and 4 cycles (after 11 and 16 weeks) for vision/skin toxicities and nail infection/mucositis, respectively. Conclusions: The oral FGFR inhibitor BGJ398 showed antitumor activity in a marker lesion study of patients with recurrent high-grade papillary NMIBC. Treatment was discontinued secondary to toxicities in all subjects, after a range of 4 to 16 weeks. Further investigation may be warranted for lower doses of oral BGJ398 or other formulations, such as intravesical delivery. Clinical trial information: NCT02657486. [Table: see text]

Purpose To evaluate the risk of cataract in the setting of AIDS. Design Prospective cohort study. Participants Subjects with AIDS free of ocular opportunistic infections throughout catamnesis. Methods From 1998 through 2008, subjects 13 years of age or older were enrolled. Demographic characteristics and clinical characteristics were documented at enrollment and semiannually. Main Outcome Measures Cataract was defined as high-grade lens opacity observed by biomicroscopy judged to be the cause of a best-corrected visual acuity worse than 20/40. Eyes that underwent cataract surgery during follow-up were considered to have developed cataract before the first visit when pseudophakia or aphakia was observed. Results Among 1606 participants (3212 eyes) at enrollment, 1.9% (95% confidence interval [CI]: 1.3%–2.7%) were observed to have cataract or prior cataract surgery. Among the 2812 eyes initially free of cataract and followed longitudinally (median follow-up, 4.6 years), the incidence of cataract was 0.37%/eye-year (95% CI: 0.26%–0.53%). In addition to age, significant cataract risk factors included prior cataract in the contralateral eye (adjusted hazard ratio [aHR], 21.6; 95% CI: 10.4–44.8), anterior segment inflammation (aHR, 4.40; 95% CI: 1.64–11.9), prior retinal detachment (aHR, 4.94; 95% CI: 2.21–11.0), and vitreous inflammation (aHR, 7.12; 95% CI: 2.02–25.0), each studied as a time-updated characteristic. Detectable human immunodeficiency virus RNA in peripheral blood was associated with lower risk of cataract at enrollment (adjusted odds ratio, 0.32; 95% CI: 0.12–0.80) but not of incident cataract (aHR, 1.58; 95% CI: 0.90–2.76). After adjustment for other factors, neither the then-current absolute CD4+ T-cell count nor antiretroviral therapy status showed consistent association with cataract risk, nor did an additive diagnosis of other comorbidities. Compared with the available population-based studies that used similar definitions of cataract, the age-specific prevalence of cataract in our cohort was higher than in 1 of 2 such studies, and the age-specific incidence of cataract surgery was higher. Conclusions Our results suggest cataract may occur earlier among patients with AIDS free of ocular opportunistic infections than in the general population. Cataract risk was associated most strongly with age and with other ocular morbidity in this population. With improved survival, the burden of cataract likely will increase for persons with the human immunodeficiency virus or AIDS.

To evaluate cataract risk in eyes of patients with AIDS and cytomegalovirus (CMV) retinitis and to identify risk factors.Prospective cohort study.Patients with AIDS and CMV retinitis.Patients 13 years of age and older were enrolled between 1998 and 2008. Demographic and clinical characteristics, slit-lamp biomicroscopy findings, and dilated ophthalmoscopy results were documented at quarterly visits. Cataract status was determined at the initial visit (prevalence) and at follow-up visits (incidence).For cataract, a high grade of lens opacity by biomicroscopy to which best-corrected visual acuity worse than 20/40 was attributed. Eyes that had undergone cataract surgery before enrollment or between visits also were counted as having cataract.Seven hundred twenty-nine eyes of 489 patients diagnosed with CMV retinitis were evaluated. Higher prevalence was observed for patients with bilateral versus unilateral CMV retinitis (adjusted odds ratio [aOR], 2.74; 95% confidence interval [CI], 1.76-4.26) and, among unilateral CMV retinitis cases, for eyes with retinitis versus without retinitis (15% vs. 1.4%; P0.0001). The age-adjusted prevalence of cataract among CMV retinitis cases was higher than that in a population-based sample (P0.0001). Cataract prevalence increased with age (aOR, 11.77; 95% CI, 2.28-60.65 for age ≥ 60 years vs. younger than 40 years) and longer duration of retinitis (aOR, 1.36; 95% CI, 1.20-1.54 per year). Among eyes with CMV retinitis initially free of cataract, the cataract incidence was 8.1%/eye-year (95% CI, 6.7%-10.0%). Prior retinal detachment was associated with higher cataract risk (if repaired with silicone oil: adjusted hazard ratio [aHR], 10.37; 95% CI, 6.51-16.52; otherwise: aHR, 2.90; 95% CI, 1.73-4.87). Large CMV retinitis lesions also were associated with higher risk of cataract (for involvement of 25-49% retinal area: aHR, 2.30; 95% CI, 1.51-3.50; for ≥ 50% involvement: aHR, 3.63; 95% CI, 2.18-6.04), each with respect to ≤ 24% involvement, as were anterior segment inflammation (aHR, 2.27; 95% CI, 1.59-3.25) and contralateral cataract (aHR, 2.52; 95% CI, 1.74-3.66).Cytomegalovirus retinitis is associated with a high absolute and relative risk of cataract. Among several risk factors, large retinal lesion size and use of silicone oil in retinal detachment repair are potentially modifiable, albeit not in all cases. Cataract is likely to be an increasingly important cause of visual morbidity in this population.

Implementation of multicenter and/or longitudinal studies requires an effective quality assurance program to identify trends, data inconsistencies and process variability of results over time. The Diabetes Control and Complications Trial (DCCT) and the follow-up Epidemiology of Diabetes Interventions and Complications (EDIC) study represent over 30 years of data collection among a cohort of participants across 27 clinical centers. The quality assurance plan is overseen by the Data Coordinating Center and is implemented across the clinical centers and central reading units. Each central unit incorporates specific DCCT/EDIC quality monitoring activities into their routine quality assurance plan. The results are reviewed by a data quality assurance committee whose function is to identify variances in quality that may impact study results from the central units as well as within and across clinical centers, and to recommend implementation of corrective procedures when necessary. Over the 30-year period, changes to the methods, equipment, or clinical procedures have been required to keep procedures current and ensure continued collection of scientifically valid and clinically relevant results. Pilot testing to compare historic processes with contemporary alternatives is performed and comparability is validated prior to incorporation of new procedures into the study. Details of the quality assurance plan across and within the clinical and central reading units are described, and quality outcomes for core measures analyzed by the central reading units (e.g. biochemical samples, fundus photographs, ECGs) are presented.

Purpose The use of gefitinib, the first drug approved to inhibit the epidermal growth factor receptor tyrosine kinase, is indicated in patients with non–small-cell lung cancer with tumors progressive after chemotherapy. The unique mechanism of action of this agent leads to distinctive patterns of response and toxicity in persons with lung cancer. Many of the principles of management relevant to gefitinib are distinct from those with conventional cytotoxic drugs. To meet this need, we present practical guidelines on the use of gefitinib in patients with non–small-cell lung cancer. Methods This article reviews gefitinib’s indications, dosing, response phenomena, and patterns of relapse in individuals with radiographic response. Results We present our recommendations for the management of rash and diarrhea caused by this agent. Conclusion This information can guide practitioners and help them inform their patients about what to expect when they receive gefitinib.

Primary ocular lymphoma (POL), a lymphoma of the globe, is a restricted form of primary central nervous system lymphoma (PCNSL) that often progresses to the brain and meninges; frequently it is misdiagnosed until central nervous system (CNS) lymphoma develops. The optimal treatment has not yet been identified. We retrospectively reviewed the course and the treatment of POL in 31 patients. Seventeen patients were treated for isolated POL (group A) and 14 were treated only after CNS disease was diagnosed (group B). The treatment in both groups consisted of systemic chemotherapy, chemotherapy plus radiotherapy (RT) or RT alone. In group A, nine patients (53%) developed CNS progression and five (29%) had ocular recurrence. In group B, seven (50%) had CNS progression and three (21%) ocular relapse. To control for diagnostic lead time, median survival was calculated from initial ocular symptoms and was 60 months in group A and 35 months in group B (P < 0.05). Ocular lymphoma responds to a variety of therapies but treatment with chemotherapy and/or ocular radiotherapy (ORT) failed to prevent CNS progression. Patients whose ocular disease was identified and treated before CNS progression had a significantly improved survival.

11039 Background: Preclinical studies suggest that imatinib resistance (IR) in GIST can be mediated by MAP-kinase activation via FGF signaling. In FGF stimulated GIST cell lines, BGJ398, a pan-FGFR inhibitor in combination with imatinib, is cytotoxic and superior to imatinib alone, or imatinib in combination with MEK-inhibition. In GIST with FGF signaling, the combination of BGJ398 and imatinib may provide a mechanism to overcome IR. Methods: This phase Ib study of BGJ398 in combination with imatinib was performed in patients (pts) with imatinib resistant advanced GIST. A standard 3+3 dosing schema was utilized to determine the recommended phase II dose. Two treatment schedules were evaluated incorporating imatinib 400mg daily continuously in combination with (A) BGJ daily 3 wks on, 1 wk off or (B) BGJ daily 1 wk on, 3 wks off. Response was evaluated by RECIST and CHOI every 8 wks x4 and then every 12 wks. Results: 16 pts enrolled. Median age 54 (range: 44-77), 81% male, median prior therapy 4 [range: 2-6, 13/16 pts had ≥ 3 prior therapies (81%)]. 12 pts received treatment on schedule A [dose level (DL)1 (BGJ 75mg), n = 6; DL-1 (BGJ 50mg), n = 3; DL-2 (BGJ 25mg), n = 3]: 3 DLTs (myocardial infarction, grade (G)4 CPK elevation, G3 ALT elevation) were observed on schedule A at DL1, hyperphosphatemia (on target effect) was not observed raising concern for therapeutic efficacy at the maximum tolerated dose. Following protocol amendment that allowed an alternative dosing schedule, 4 pts enrolled on schedule B [DL1 (BGJ 75mg), n = 3; DL2 (BGJ 100mg), n = 1]: one DLT occurred (G3 intra-abdominal hemorrhage) at DL2. The most common non-DLT G3/4 toxicity was HTN (2/16pts) and G2 toxicity was prolonged QTc interval (3/16pts). Of the 12 pts with evaluable CT scans, stable disease (SD) was the best response observed in 7 pts by RECIST and 9 pts by CHOI. 3pts achieved SD for > 6 months. 2 pts remain on study at data cut-off (range: 1 – 67 wks). Median progression free survival is 8 weeks. Pharmacokinetic analysis of imatinib and BGJ is forthcoming. Conclusions: In heavily pre-treated pts, durable disease control was observed in 3/16 pts. This signal of efficacy suggests that further evaluation of FGF signaling in the development of IR is warranted. Clinical trial information: NCT02257541.

Refractive error (RE) is a complex, multifactorial disorder characterized by a mismatch between the optical power of the eye and its axial length that causes object images to be focused off the retina. The two major subtypes of RE are myopia (nearsightedness) and hyperopia (farsightedness), which represent opposite ends of the distribution of the quantitative measure of spherical refraction. We performed a fixed effects meta-analysis of genome-wide association results of myopia and hyperopia from 9 studies of European-derived populations: AREDS, KORA, FES, OGP-Talana, MESA, RSI, RSII, RSIII and ERF. One genome-wide significant region was observed for myopia, corresponding to a previously identified myopia locus on 8q12 (p = 1.25×10-8), which has been reported by Kiefer et al. as significantly associated with myopia age at onset and Verhoeven et al. as significantly associated to mean spherical-equivalent (MSE) refractive error. We observed two genome-wide significant associations with hyperopia. These regions overlapped with loci on 15q14 (minimum p value = 9.11×10-11) and 8q12 (minimum p value 1.82×10-11) previously reported for MSE and myopia age at onset. We also used an intermarker linkage- disequilibrium-based method for calculating the effective number of tests in targeted regional replication analyses. We analyzed myopia (which represents the closest phenotype in our data to the one used by Kiefer et al.) and showed replication of 10 additional loci associated with myopia previously reported by Kiefer et al. This is the first replication of these loci using myopia as the trait under analysis. "Replication-level" association was also seen between hyperopia and 12 of Kiefer et al.'s published loci. For the loci that show evidence of association to both myopia and hyperopia, the estimated effect of the risk alleles were in opposite directions for the two traits. This suggests that these loci are important contributors to variation of refractive error across the distribution.

Purpose To report uveitis associated with human immunodeficiency virus (HIV) infection and to suggest guidelines for treatment. Methods Six HIV-seropositive patients (10 eyes) with anterior or posterior uveitis or both were evaluated. After ineffective prolonged treatment with systemic and topical corticosteroids, specific systemic antiretroviral therapy with zidovudine was initiated in all patients. Aqueous humor was cultured in three eyes of three patients, and vitreous humor was cultured in one eye of one patient. Results In all 10 eyes of six patients, there was resolution of inflammation in 10 to 42 days after commencement of treatment with zidovudine (600 to 800 mg/day), despite no or minimal response to corticosteroids. Cultures of aqueous humor from three eyes of three patients and culture of vitreous humor from one eye of one patient were positive for HIV; no other organism was isolated. Systemic evaluation disclosed no other identifiable cause for the uveitis in any patient. Conclusions Infection with HIV appears to be a cause of uveitis. A trial of zidovudine may be warranted in HIV-seropositive patients with uveitis that is poorly responsive to cortico-steroid treatment when no other cause is identified. The efficacy of other retroviral agents was not determined.

Vitreous specimens from 14 HIV-1 infected persons undergoing medically indicated vitrectomy were assayed for the presence of infectious HIV-1 and viral tropism. Human primary fetal astrocytes, adult lymphocytes, or macrophages were exposed to vitreous in culture and and cells were then assayed for HIV-1 DNA by polymerase chain reaction amplification. We found that 11 of 14 patients tested carried ocular HIV-1 which replicated in one or more primary cell types; of the 13 vitreous samples tested in astrocytes, eight contained transmissible HIV-1. The three patients with no culturable ocular virus were in antiviral therapy at the time of vitrectomy. Comparison of envelope V3 sequences from astrocytes infected in culture to that in uncultured blood cells revealed 21% sequence divergence indicating that ocular HIV-1 transmitted to astrocytes was not recently derived from virus present in the blood. Two ocular samples transmissible to astrocytes were tested further and found capable of sustained replication by serial passage to uninfected astrocytes. However, the viral structural proteins produced by infected astrocytes were abnormal, p24 was absent and higher molecular weight Gag proteins were present. We conclude that the eye is a central nervous system compartment which frequently contains HIV-1 capable of replication in human astrocytes.

The pharmacodynamic relationship between a range of foscarnet exposure measurements obtained from studying nine patients receiving ongoing maintenance therapy for cytomegalovirus retinitis and a range of efficacy values (days to retinitis progression) obtained by independent examination of serial retinal photographs from the same nine patients was analyzed. In the resulting proportional hazards models, the foscarnet area under the concentration-time curve approached statistical significance (P = 0.11) as a predictor of decreased risk of retinitis progression.

The efficacy and safety of a combination of ganciclovir plus GM-CSF was evaluated in AIDS patients with cytomegalovirus retinitis. In phase A, patients were randomized to receive ganciclovir, 5 mg/kg every 12 h for 14 days followed by 5 mg/kg daily, with (n=24) or without (n=29) GM-CSF (1–8 µg/kg daily subcutaneously) to maintain absolute neutrophil counts between 2500 and 5000 cells/µl. In phase B, after 16 weeks zidovudine was added to the regimen of 16 patients receiving ganciclovir plus GM-CSF and 20 receiving ganciclovir alone. At this stage, GM-CSF was added to the treatment protocol of any patient receiving ganciclovir plus zidovudine who became neutropenic. In phase A, patients in the ganciclovir plus GM-CSF group had significantly higher neutrophil counts than ganciclovir-alone patients (p=0.0001). Overall, 12.5 % of patients treated with GM-CSF developed neutropenia (absolute neutrophil counts

Thirty-two patients with AIDS and previously untreated cytomegalovirus retinitis completed an induction course of foscarnet, 60 mg/kg every 8 h for 14 days, had retinitis stabilize, and were then randomly assigned to receive foscarnet maintenance as either a 90- or 120-mg/kg/day infusion administered over 2 h. Median survival was 157 and 336 days for the 90- and 120-mg/kg/day groups, respectively (P < .001). In an independent, masked analysis of retinal photographs, median time to progression of retinitis was 31 versus 95 days (P = .13). Daily intravenous foscarnet at a dose of 120 mg/kg (adjusted for renal function) resulted in significantly longer survival and tended to increase time to retinitis progression compared to the standard 90-mg/kg/day maintenance dose. Although a substantial increase in the risk of serious toxicity at the 120-mg/kg/day dose was not observed, the small sample size in this trial limited the power to detect differences that might be clinically important.

The majority of AIDS patients will develop ocular complications at some point during the course of their illness. The most common complications involve the retina. Accurate diagnosis of noninfectious and infectious (especially CMV) retinopathy is extremely important as most forms of infectious retinitis can be treated, albeit not without significant complications in many cases. Close cooperation between the ophthalmologist and internist is essentially to ensure that timely therapeutic intervention, which can dramatically reduce the risk of visual impairment and blindness, can be initiated. AIDS-related diseases of the central nervous system, especially nonviral infections, are often associated with abnormalities of ocular function. Assessment of visual acuity, visual fields, extraocular movements, pupillary reflexes, color perception, and the condition of optic nerve and retina is important for accurate diagnosis.

A Phase I-II trial of gallium nitrate was conducted in 40 patients with bidimensionally measurable urothelial tract tumors who had failed to respond to combination chemotherapy with methotrexate, vinblastine, doxorubicin, and cisplatin. Partial responses were observed in 4 of 23 patients (17.4%) who received 350 mg/m2/d or more for 5 days by continuous intravenous infusion. In two additional patients who received 350 mg/m2/d or more, a minor response and a mixed response were observed. The median duration of response was 4 months (range, 2 to 8 months). A dose-response relationship was suggested because no responses were observed in 17 patients who received less than 350 mg/m2/d. Myelosuppression was minimal. The dose-limiting toxic reaction was a reversible optic neuropathy that occurred in 3 of 11 patients who received 400 mg/m2/d. Further evaluation of infusional gallium nitrate is warranted in patients with urothelial tract malignant tumors.

Familial polyposis coli (FPC) is hereditary condition that conveys a virtual 100% risk for the development of colon cancer in the untreated patient. A total of 56 patients with FPC underwent complete ophthalmic examination. Highly pleomorphic pigmented retinal lesions were identified bilaterally in 52% (n = 29) and unilaterally in 14% (n = 8) of our subjects. In all, 33 patients had one or more extracolonic expressions associated with FPC, including desmoids, osteomas, epidermoid cysts, lipomas, fibromas, and upper gastrointestinal tract polyps. In 15 patients, pigmented fundus lesions were the only extracolonic manifestations. No significant association between eye findings and other extracolonic manifestations could be established. The presence or absence of pigmented fundus lesions was found to cluster within families. Pigmented fundus lesions are probably a variably penetrant expression of the polyposis gene and do not appear to be specifically associated with subgroups of inherited polyposis syndromes such as Gardner's syndrome.

OBJECTIVE To examine the persistence of the original treatment effects 10 years after the Diabetes Control and Complications Trial (DCCT) in the follow-up Epidemiology of Diabetes Interventions and Complications (EDIC) study. In the DCCT, intensive therapy aimed at near-normal glycemia reduced the risk of microvascular complications of type 1 diabetes mellitus compared with conventional therapy. METHODS Retinopathy was evaluated by fundus photography in 1211 subjects at EDIC year 10. Further 3-step progression on the Early Treatment Diabetic Retinopathy Study scale from DCCT closeout was the primary outcome. RESULTS After 10 years of EDIC follow-up, there was no significant difference in mean glycated hemoglobin levels (8.07% vs 7.98%) between the original treatment groups. Nevertheless, compared with the former conventional treatment group, the former intensive group had significantly lower incidences from DCCT close of further retinopathy progression and proliferative retinopathy or worse (hazard reductions, 53%-56%; P < .001). The risk (hazard) reductions at 10 years of EDIC were attenuated compared with the 70% to 71% over the first 4 years of EDIC (P < .001). The persistent beneficial effects of former intensive therapy were largely explained by the difference in glycated hemoglobin levels during DCCT. CONCLUSION The persistent difference in diabetic retinopathy between former intensive and conventional therapy ("metabolic memory") continues for at least 10 years but may be waning. TRIAL REGISTRATION (clinicaltrials.gov) Identifiers: NCT00360815 and NCT00360893.

Rhegmatogenous retinal detachments are associated with cytomegalovirus (CMV) retinitis and the use of the ganciclovir intraocular device. Pars plana vitrectomy with silicone oil tamponade is the preferred technique to repair such detachments. The authors describe the use of pneumatic retinopexy as part of a treatment strategy in the management of multiple retinal detachments in a patient with CMV retinitis treated with ganciclovir implants. Pneumatic retinopexy may benefit patients when the causative retinal break is superior and is located in an area of retina uninvolved with CMV infection, because it can be used to delay surgical intervention. [Ophthalmic Surg Lasers 1998;29:244-246.]

Primary ocular lymphoma (POL), a lymphoma of the globe, is a restricted form of primary central nervous system lymphoma (PCNSL) that often progresses to the brain and meninges; frequently it is misdiagnosed until central nervous system (CNS) lymphoma develops. The optimal treatment has not yet been identified. We retrospectively reviewed the course and the treatment of POL in 31 patients. Seventeen patients were treated for isolated POL (group A) and 14 were treated only after CNS disease was diagnosed (group B). The treatment in both groups consisted of systemic chemotherapy, chemotherapy plus radiotherapy (RT) or RT alone. In group A, nine patients (53%) developed CNS progression and five (29%) had ocular recurrence. In group B, seven (50%) had CNS progression and three (21%) ocular relapse. To control for diagnostic lead time, median survival was calculated from initial ocular symptoms and was 60 months in group A and 35 months in group B (P0.05). Ocular lymphoma responds to a variety of therapies but treatment with chemotherapy and/or ocular radiotherapy (ORT) failed to prevent CNS progression. Patients whose ocular disease was identified and treated before CNS progression had a significantly improved survival.

OBJECTIVE To evaluate the efficacy of the ganciclovir implant in the setting of silicone oil vitreous substitute. MATERIALS AND METHODS The authors retrospectively reviewed the charts of 19 patients with cytomegalovirus retinitis who had both a ganciclovir implant and silicone oil vitreous substitute. None of the patients was receiving highly active antiretroviral therapy during the study period. Kaplan-Meier analysis was used to evaluate time to progression in eyes with the ganciclovir implant and silicone oil. RESULTS In all eyes, the ganciclovir device implantation preceded or coincided with silicone injection. Kaplan-Meier analysis revealed that time to 25% failure from the date of the presence of both the implant and oil was 129 days. Time to 25% failure from the date of ganciclovir device implantation was 179 days. CONCLUSIONS These results compare favorably with conventional treatment. The ganciclovir implant can be a useful treatment modality in eyes with silicone oil.

Article abstract A 49-year-old woman with immunoglobulin Gκ multiple myeloma developed progressive visual loss with bilateral upper and lower central arcuate scotomas. Funduscopic and electrophysiologic studies indicated bilateral optic neuropathy. The immunoglobulin G fraction of the patient’s serum reacted with retinal ganglionic cells in bovine retina. The visual abnormalities remitted after myeloablative chemotherapy and disappearance of the paraprotein.

Article abstract-We established the frequency of Horner's syndrome (HS) in 248 elective patients after coronary artery bypass surgery. Patients were evaluated neurologically pre- and post-operatively and 6 months after surgery. Nineteen patients (7.7%) developed unilateral HS postoperatively, 12 involving the left eye. The finding persisted in 10 patients (4%) at 6 months. When assessed 2 to 6 days, or 6 months, postoperatively, HS tended to be isolated and not associated with C8/T1 plexopathy. Among nondiabetic subjects, hypertensive patients had a higher frequency of HS than normotensive patients (10.6% versus 2.9%, p = 0.05). Among normotensive subjects, diabetic patients had a higher frequency than nondiabetic patients (15% versus 2.9%, p = 0.08). There was no association between HS, age, sex, internal mammary artery grafting, or length of cardiopulmonary bypass time. In summary, HS is a common and sometimes persistent complication of coronary artery bypass surgery. Hypertensive, and possibly diabetic, patients appear to be at greatest risk for developing HS.NEUROLOGY 19;: 181-184

Sera obtained from AIDS patients with cytomegalovirus (CMV) retinitis before and after treatment with foscarnet, AIDS patients with human immunodeficiency virus (HIV) retinopathy, AIDS patients without retinal disease, and normal healthy controls with and without positive CMV serologies were assayed for the presence of antibodies against the 200-kDa outer, 160-kDa middle, and 68-kDa core subunits of the neurofilament triplet. Additional studies were performed to determine the presence of antibodies reactive with proteins extracted from crude human retinal antigen preparations. Antibodies against the 200-, 260-, and 68-kDa proteins of the neurofilament triplet were detected in 15 of 15 AIDS patients with CMV retinitis. The expression of these antibodies was unaffected, qualitatively, by successful treatment with foscarnet. In contrast, only 30% of patients with HIV retinopathy unrelated to CMV, fewer than 35% of AIDS patients with positive CMV titers but without evident retinitis, and fewer than 25% of healthy controls with positive or negative CMV titers possessed antibodies against any of the triplet proteins (P < 0.001). Antibodies against several clusters of retinal antigens were also identified in the sera of patients with CMV retinitis. In summary, the data indicate that retinal elements damaged by CMV infection induce an antibody response against the 200-, 160-, and 68kDa components of the neurofilament triplet as well as other, as yet undefined retinal antigens.

Cytomegalovirus (CMV) retinitis is the most common ocular opportunistic infection in patients with acquired immunodeficiency syndrome (AIDS). The disease is inexorably progressive when untreated, making early detection and prompt treatment essential for preservation of functional vision. The retinitis tends to be unilateral at presentation but often becomes bilateral as it progresses. Lesions may be unifocal or multifocal and may appear in the posterior retina or peripheral retina. Primary ophthalmoscopic features of CMV retinitis include white granular zones of retinal necrosis, variable degrees of associated hemorrhage, and low-grade iritis and vitritis. Differential diagnosis is aided by characteristic features of CMV retinitis and other AIDS-related retinopathies. Initial treatment with ganciclovir or foscarnet has been found to stabilize retinitis, and maintenance therapy with either has been shown to prolong the time to retinitis progression. Further studies should help to determine the optimal approach to treatment of the disease.

Primary central nervous system lymphoma (PCNSL), an uncommon tumor, is occurring with increasing frequency. Conventional therapy with corticosteroids and cranial radiotherapy (RT) usually gives a dramatic initial response, but median survival is only 10 to 18 months. Chemotherapy is more successful in comparable systemic lymphoma and has been employed for PCNSL at relapse, causing remission but not cure. Between June 1985 and June 1988, we prospectively staged 32 patients with PCNSL at Memorial Sloan-Kettering Cancer Center and treated 28 on a new protocol that combined chemotherapy and radiotherapy at diagnosis. None had occult systemic lymphoma, but 19% had ocular and 69% had definite or probable leptomeningeal lymphoma. There were no complications in 19 stereotactic biopsies, but 4/10 patients who had a complete resection suffered a severe postoperative deficit. Four patients received RT alone, and 28 received chemotherapy and cranial RT, 17 of whom (group A) received a combination regimen using pre-RT systemic (1 g/m2) and intra-Ommaya methotrexate (MTX), 4,000 cGy whole-brain RT with a 1,440 cGy boost, and 2 courses of post-RT high-dose cytosine arabinoside; 5 other patients received an identical regimen but with a decreased dose of MTX (200 mg/m2). Sixty-three percent of assessable patients had a response to MTX independent of corticosteroid and prior to RT. Eighteen of 26 (69%) assessable patients who received combined therapy are alive with a median follow-up of 25.4 months. Twelve of 16 (75%) assessable group A patients are alive in the same period. Chemotherapy-related toxicity was minimal, and no late toxicities have occurred to date.(ABSTRACT TRUNCATED AT 250 WORDS)

Purpose To report a case in which we treated cytomegalovirus retinitis using an intravitreal ganciclovir sustained-release device in a patient negative for the human immunodeficiency virus, with a history of myeloproliferative syndrome with myelofibrosis and profound immunosuppression after allogeneic bone marrow transplantation. Methods Case report. Review of medical records and fundus photographs. Results After the ganciclovir device was implanted, the cytomegalovirus retinitis did not progress, and visual acuity improved. We removed the device 9 months after implantation. Conclusions The ganciclovir sustained-release device may be useful for treating cytomegalovirus retinitis in patients without the acquired immunodeficiency syndrome who are profoundly immunosuppressed and fail conventional intravenous therapy. If immune suppression is of limited duration, the device can be removed.

Purpose To report treatment of bilateral cytomegalovirus (CMV) retinitis in an 11-year-old girl with acquired immunodeficiency syndrome (AIDS). Method Case report describing the use of intravitreal ganciclovir sustained-release devices to treat CMV retinitis, involving zones 1 through 3, which progressed despite single and combination intravenous therapy with ganciclovir and foscarnet. Results Stabilization with no active CMV retinitis was achieved after bilateral implantation of intravitreal sustained-release ganciclovir devices. There was no reactivation of the retinitis during the 5 months of follow-up. Conclusion Sustained-release ganciclovir implants can be used to achieve local control of CMV retinitis in the pediatric patient.

Background: The Foscarnet-Ganciclovir Cytomegalovirus Retinitis Trial compared the use of either ganciclovir or foscarnet for the initial treatment of cytomegalovirus retinitis in patients with the acquired immunodeficiency syndrome. We previously reported that patients treated with foscarnet lived longer but were more likely to have their treatment switched, the latter suggesting foscarnet may not have been as well tolerated as ganciclovir. This study compared the morbidity and toxic reactions reported during the trial. Methods: Two hundred thirty-four patients with the acquired immunodeficiency syndrome and previously untreated cytomegalovirus retinitis at 11 university centers were randomly assigned to receive intravenously either foscarnet (n=107) or ganciclovir (n=127). Medical histories, laboratory tests, and drug treatment histories during the first 6 months of treatment were analyzed. Results: Neutropenia was more common in patients assigned to ganciclovir than to foscarnet (34% vs 14%;P=.001). Patients assigned to foscarnet reported more infusion-related symptoms (58% vs 24%;P .001); they also experienced a trend toward more nephrotoxic effects (13% vs 6%;P=.082) and electrolyte abnormalities. The incidence of seizures was similar in both groups (foscarnet, 12%; ganciclovir, 9%;P=.511). Patients assigned to foscarnet were more likely to be switched to the alternative treatment (foscarnet to ganciclovir, 46%; ganciclovir to foscarnet, 11%;P Conclusions: Compared with ganciclovir, the use of foscarnet was more frequently limited by the occurrence of toxic reactions. However, these toxic reactions rarely had long-term sequelae. In light of the previously reported survival benefit seen in patients treated with foscarnet, these data support the use of foscarnet for the initial treatment of cytomegalovirus retinitis. (Arch Intern Med. 1995;155:65-74)

Cytomegalovirus (CMV) retinal infection has become a major cause of morbidity for severely immunocompromised patients with the acquired immunodeficiency syndrome (AIDS). Cytomegalovirus retinitis is currently the leading cause of decreased visual acuity and loss of visual field among American patients with AIDS. In this population, retinal infection by CMV occurs predictably as a late complication when helper T-lymphocyte (CD4) counts drop below 0.05×10 9 /L (50 cells per microliter). 1 Before the AIDS epidemic, CMV was an infrequent cause of retinitis in immunosuppressed patients undergoing organ transplantation and in patients with endstage cancer. 2 We report herein an HIV-negative patient with myasthenia gravis and a normal CD4 count (0.86×10 9 /L) who developed CMV retinitis while being treated with azathioprine. Report of a Case. The patient was a 56-year-old Asian woman who was referred to us with bilateral, increasingly blurred vision of 3 weeks' duration. The patient denied subjective

A patient with human immunodeficiency virus (HIV) type 1 infection developed chronic iridocyclitis and anterior vitritis that were poorly responsive to topical and systemic corticosteroid therapy. Anterior chamber paracentesis was performed and HIV was isolated from culture of aqueous humor. Subsequent treatment with oral zidovudine resulted in resolution of the iridocyclitis and vitritis and full functional recovery of the eye. This case suggests that HIV may be a cause of uveitis responsive to systemic zidovudine therapy.

Using radioimmunoassay technique, levels of leukotriene B4 and C4 (LTB4 and LTC4) in the aqueous humor of rabbit eyes were measured following experimental nonpenetrating ocular trauma. Slit lamp examination showed a time-dependent increase of flare, cells, and fibrin in the anterior chamber of the traumatized eyes. Polymorphonuclear (PMN) leukocyte influx into the aqueous humor was not seen at 6 hours but increased significantly in traumatized eyes after 12 hours. No inflammatory cells were observed in control eyes. Histopathologic studies demonstrated injuries of the ciliary body, ruptures of the retina and choroid, with intraocular hemorrhage. LTB4 values peaked at 6 hours, prior to PMN cell infiltration and remained significantly higher than controls, which remained undetectable at all intervals after injury. LTC4 values also peaked by 6 hours in the traumatized eyes. These data demonstrate that elevations in LTB4 and LTC4 are associated with blunt trauma, and this precedes PMN cell infiltration. Leukotrienes may play a role in the early inflammatory response following concussive ocular injuries.

Objective: To determine the efficacy and safety of intravitreal injection of ganciclovir for active cytomegalovirus (CMV) retinitis in AIDS patients who are intolerant of systemic ganciclovir therapy. Methods: An open-labeled trial of intravitreal ganciclovir induction and maintenance therapy was conducted in outpatient clinics of five AIDS Clinical Trials Units. Sixteen eyes of 11 patients were treated; 11 eyes of eight patients were included in the analysis. Patients were treated with a series of two intravitreal injections per week for the first 3 weeks (induction period), followed by one injection per week until an endpoint was reached or for a total of 24 weeks. Each injection contained 200 μg ganciclovir in a total volume of 0.1 mL, administered through a 30-gauge needle. The primary endpoint measures were the time to retinitis progression as evidenced by the development of a new lesion or progression by more than 750 μm of a preexisting lesion, and progression of CMV as evidenced by development of active disease in the untreated eye or at an extraocular site. Other outcome measures were changes in visual acuity and adverse events related to the intravitreal injections. Results: All of the treated eyes responded to induction therapy, and three eyes were successfully reinduced a total of four times. Median time to retinitis progression was 8.9 weeks (range, 6–20 wk). Cytomegalovirus disease of the untreated fellow eye or at an extraocular site occurred in four of seven patients (57%) for whom adequate follow-up data exist, at a mean of 11.7 weeks of study. Intravitreal injections were well-tolerated, and all complications were transient and reversible. Conclusions: Intravitreal ganciclovir therapy is effective for the treatment of active CMV retinitis, with median times to retinitis progression comparable to those achieved with systemic therapy, and may be administered with minimal complications. However, the frequent occurrence of CMV disease in the untreated fellow eye and at extraocular sites suggests that when used as sole therapy, intravitreal treatment should be given for short periods of time, when systemic therapy is not possible.

17 weeks, she was again referred for AFP determinations which showed 224 ng. per milliliter in maternal serum and l ,249 ng. per milliliter in amniotic fluid. The slope of values in maternal semm had risen steeply from approximately the twenty-fifth percentile to the ninetieth percentile, and the amniotic fluid levels were much greater than the expected 200 ng. per milli­ liter. A sonogram showed a biparietal diameter of 8.5 em., compatible with a date of 35 weeks and a marked excess of amniotic fluid, but there was no evidence to suggest a menin­ gomyelocele. An amniogram after removal of 30 c.c of am­ niotic fluid and instillation of Renografin-60 failed to show any contrast material in the small bowel on two sets of films taken three hours apart. This was thought to be due to dilu­ tion of the contrast medium with excessive fluid. No gross malformations of the extremities, head, or vertebral column were visualized. Besides the hydramnios, the only abnormal findings were the AFP results which at 39 1

Low viscosity perfluorocarbon liquids were used as an intraoperative tool during vitrectomy for retinal detachment (RD) after penetrating ocular trauma. These liquids are immiscible with water and have specific gravities from 1.8 to 1.9. Intraoperatively, the perfluorocarbon liquids flattened the retina in 14 eyes by displacing the subretinal fluid through peripheral breaks. Posterior retinotomy was not required for internal drainage of subretinal fluid. Pooled subretinal fluid was displaced from the macular area in five patients. The perfluorocarbon bubble mechanically stabilized the retina during epiretinal membrane dissection. The perfluorocarbon liquid was removed and replaced perfluorocarbon gas or silicone oil. In 11 patients followed for more than 6 months after the final surgery, eight (73%) eyes were anatomically successful, with six (54.5%) gaining visual acuity of 20/400 or better.

Ophthalmic examinations were performed on 56 patients with validated familial adenomatous polyposis (FAP) for hyperpigmented defects of the retinal pigment epithelium. Such lesions were seen bilaterally in 29 patients (52%) and unilaterally in 8 patients (14%). Of the 56 patients, 33 had one or more of the extracolonic expressions associated with Gardner syndrome. We found retinal lesions in 8 patients without any of the expressions of Gardner syndrome. No association was found between Gardner syndrome and the retinal lesions when these patients were compared to patients without any stigmata of Gardner syndrome, nor was any significant association found when each of the expressions was compared individually with the presence of the pigmented retinal lesions. The presence or absence of eye findings were seen to cluster within families. There was no association with sex. Fundus lesions are apparently a variable expression of the FAP gene and are not specifically associated with Gardner syndrome.

A 32-year-old patient with acquired immune deficiency syndrome (AIDS) was evaluated for bilateral visual loss accompanied by uveitis, vitritis and retinochoroiditis. Diagnostic vitrectomy was performed on the right eye, and the diagnosis of ocular toxoplasmosis made. Central nervous system involvement was suggested by ring enhancing lesions on CT scan. The patient improved on a pyrimethamine, sulfadiazine and clindamycin, but succumbed to disseminated toxoplasmosis when treatment was discontinued.

The safety and efficacy of intravitreously administered ganciclovir sodium as sole treatment for cytomegalovirus retinitis complicating the acquired immunodeficiency syndrome was studied prospectively in seven patients. All but one of the patients had bilateral cytomegalovirus retinitis and none were able to tolerate therapy with systemically administered ganciclovir because of myelosuppression in six patients and hepatotoxicity in one patient. Intravitreal ganciclovir therapy was discontinued in two patients within the initial 2-week induction phase because of severe intractable thrombocytopenia in one patient and retinal detachment in the other. The retinal detachment could not be conclusively attributed to the injections and was probably a secondary complication of cytomegalovirus retinitis. The remaining five patients were treated weekly, with the course of therapy ranging from a minimum of 14 weeks (18 injections) to a maximum of 56 weeks (58 injections). The patients were followed up for an average of 23.5 weeks. All eyes responded to intravitreal therapy initially, while the six untreated control eyes with cytomegalovirus retinitis all demonstrated progression of disease. Two eyes relapsed while receiving intravitreal doses of 200 micrograms of ganciclovir sodium and were subsequently treated with 300 micrograms of ganciclovir sodium per injection. One eye responded to this regimen, while in the other one the disease progressed. In the long-term treatment group, one eye developed Staphylococcus epidermidis endophthalmitis, which was treated with vitrectomy and intravitreal and systemic antibiotics.

To the Editor. —Opportunistic intraocular infections caused by a wide variety of pathogens have been described as complications of the acquired immunodeficiency syndrome (AIDS). Candida endophthalmitis, a commonly recognized complication of disseminated candidiasis, is often seen in the setting of neutropenia or impaired neutrophil function, but rarely as the sequela of a deficiency of cell-mediated immunity. We present a case of Candida albicans endophthalmitis in a bisexual male with AIDS and no history of drug abuse. Report of a Case. —A 50-year-old Hispanic man with AIDS was admitted for evaluation of chronic dermatitis of unknown origin, anemia, and low-grade fever. Shortly after admission, an ophthal

To the Editor. —Treatment of progressive cytomegalovirus (CMV) retinitis with intravitreal injections of ganciclovir has been advocated as an effective and safe form of therapy in patients in whom severe neutropenia precludes adequate intravenous ganciclovir therapy. 1,2 A patient with acquired immunodeficiency syndrome (AIDS) complicated by progressive CMV retinitis of the right eye underwent a course of intravitreal treatment with ganciclovir because of persistent neutropenia resulting from intravenous ganciclovir therapy. During the ninth week of therapy the patient developed a bacterial endophthalmitis that required pars plana vitrectomy and a course of systemic antibiotic therapy. Report of a Case. —A 36-year-old homosexual man was diagnosed as having AIDS in 1987 when he developed Pneumocystis carinii pneumonia. At this time he was found to have CMV retinitis of the right eye, which was treated with an initial induction course of ganciclovir followed by maintenance therapy. The progression of the retinitis was arrested