Assessment of off-label use of denosumab 60 mg injection during the early postmarketing period using health insurance claims data.

UNLABELLED: Off-label use of denosumab 60 milligram (mg) injection was assessed within an administrative claims database. The completeness of claims to assess off-label use was investigated with medical record review. Potential denosumab 60 mg off-label use was observed based on claims, but many had evidence of on-label indications based on medical record review. INTRODUCTION: Denosumab 60 mg injection is approved in the USA to treat patients at high fracture risk due to postmenopausal osteoporosis, male osteoporosis, and hormone therapy for the treatment of prostate and breast cancers. Its RANK ligand-inhibiting effect makes it a candidate for the off-label treatment of other conditions mediated by the rate of bone resorption by osteoclasts. To better understand its utilization patterns, we assessed off-label use of denosumab 60 mg within an administrative claims database. METHODS: Definite, probable, and possible denosumab 60 mg users were identified during the early postmarketing period within a claims database of a US healthcare insurer. Medical record review confirmed a sample of these users. Off-label use among definite and probable users and all chart-confirmed users was classified using claims-derived age, dose interval, and diagnosis and treatment received relative to the administration date. Among chart-confirmed users classified as off-label, patient characteristics related to treatment indication were abstracted from medical records to investigate the completeness of claims to study off-label medication use. RESULTS: Off-label use was identified based on claims in approximately 25 % of definite and probable denosumab 60 mg users and 35 % of chart-confirmed users. Medical record review identified evidence of on-label indications in 81 % of chart-confirmed users classified as off-label in claims. CONCLUSIONS: Many of the off-label denosumab 60 mg users had diagnoses or treatment consistent with on-label indications based on medical record review, suggesting these are under-recorded in claims data. It is warranted to be cautious when using administrative databases to assess off-label medication use.

Correlation of fibrosis and transforming growth factor-beta type 2 levels in the eye.

Approximately 1 out of every 10 eyes undergoing surgery for retinal detachment develops excessive intraocular fibrosis that can lead to traction retinal detachment and ultimate blindness. This disease process has been termed proliferative vitreoretinopathy (PVR). The ability to monitor and grade this fibrotic response accurately within the eye as well as the ability to aspirate vitreous cavity fluid bathing the fibrotic tissue makes this an ideal setting in which to investigate the development of fibrosis. Although laboratory studies have recently shown that transforming growth factor-beta (TGF-beta) can enhance fibrosis, little clinical evidence is yet available correlating the level of this or other growth factors with the degree of fibrosis in a clinical setting. We have found that vitreous aspirates from eyes with intraocular fibrosis associated with PVR have more than three times the amount of TGF-beta (1,200 +/- 300 pM [SEM]) found in eyes with uncomplicated retinal detachments without intraocular fibrosis (360 +/- 91 pM [SEM]). Using an in vitro assay, 84-100% of the TGF-beta activity could be blocked with specific antibodies against TGF-beta 2, whereas only 10-21% could be blocked by specific antibodies against TGF-beta 1. TGF-beta 1 was used in an animal model of traction retinal detachment. Since beta 1 and beta 2 have essentially identical biologic effects and only human beta 1 was available in quantities required, beta 1 was chosen for these in vivo studies. The injection of TGF-beta1 plus fibronectin (FN) but not TGF-beta1 alone into the vitreous cavity of rabbits resulted in the increased formation of intraocular fibrosis and traction retinal detachments as compared to control eyes. In previous studies, intravitreal FN levels were also found to be elevated in eyes with intraocular fibrosis.

Diagnosis of renal cancer by molecular urinalysis.

BACKGROUND: Organ-confined renal malignancies can be cured in the majority of patients, whereas more extensive lesions have a poor prognosis. We sought to develop a noninvasive test for renal cancer detection based on a novel molecular approach. METHODS: Matched urine and serum DNA samples were obtained before surgery from 30 patients with clinically organ-confined solid renal masses (25 with malignant tumors and five with tumors of low malignant potential) and were subjected to microsatellite analysis. Serum samples and urine samples obtained from 16 individuals without clinical evidence of genitourinary malignancy served as controls. RESULTS: Nineteen (76%) of the 25 patients with malignant tumors were found to have one or more microsatellite DNA alterations in their urine specimen, and 15 (60%) were found to have alterations in their serum DNA by microsatellite analysis. In every case, the microsatellite changes in urine or serum were identical to those found in the primary tumor. Three of five patients with tumors of low malignant potential were found to have DNA alterations in their urine, but none displayed alterations in their serum. Moreover, microsatellite alterations were not identified in either the urine or the serum samples from normal control subjects and patients with hematuria due to nephrolithiasis (renal stones). CONCLUSION: These data suggest that microsatellite DNA analysis of urine specimens provides a potentially valuable tool for the early detection of resectable kidney cancer. Furthermore, microsatellite analysis of serum samples reveals evidence of circulating tumor-specific DNA in approximately half of these patients and may reflect the propensity of these tumors to spread to distant sites at an early stage.

Association of HLA profiles with early plasma viral load, CD4+ cell count and rate of progression to AIDS following acute HIV-1 infection. Multicenter AIDS Cohort Study.

BACKGROUND: Host genetic factors, such as HLA alleles, play an important role in mediating the course of HIV-1 disease progression through largely undefined mechanisms. OBJECTIVES: To examine the association of HLA markers with HIV-1 RNA plasma viral load and other factors associated with course of disease progression in HIV-1 infection. DESIGN AND METHODS: A group of 139 HIV-1 seroconverters from the Multicenter AIDS Cohort Study had been typed for a variety of HLA markers. HIV-1 RNA plasma viral load was measured from frozen plasma specimens obtained approximately 9 months following seroconversion. CD4+ cell counts were available from the same study visit. Statistical analysis was performed using survival techniques and linear regression models to quantify the relative associations of an HLA score profile, HIV-1 RNA plasma viral load, CD4+ cell count and age with each other and with rate of progression to AIDS and death. RESULTS: Cox proportional hazards models showed statistically significant differences in time to AIDS by HLA score profile category per unit increase [relative hazard (RH), 0.64; P < 0.0001], HIV-1 RNA plasma viral load per 10-fold increase (RH, 2.04; P = 0.0003), and CD4+ cell count per 100 cell (x 10(6)/l) increase (RH, 0.90; P = 0.02). Multivariate linear regression showed that viral load was 39% lower (P = 0.0001) for each unit increase in HLA score profile and 13% lower (P = 0.002) for each 100 cell (x 10(6)/l) increase in CD4+ cell count. CONCLUSION: The means by which the HLA score profile influences the time to AIDS is probably through immunologic responses that affect the rate of HIV-1 replication, as manifested by the HIV-1 RNA plasma viral load during the first 6-12 months following acute infection.

Ex vivo culture of cord blood CD34+ cells expands progenitor cell numbers, preserves engraftment capacity in nonobese diabetic/severe combined immunodeficient mice, and enhances retroviral transduction efficiency.

Ex vivo culture of hematopoietic stem/progenitor cells could potentially improve the efficacy of human placental/umbilical cord blood (CB) in clinical hematopoietic stem cell (HSC) transplantation and allow gene transduction using conventional retroviral vectors. Therefore, we first examined the effects of a 7-day period of ex vivo culture on the hematopoietic capacity of CB CD34+ cells. Medium for the ex vivo cultures contained either serum and six recombinant human hematopoietic growth factors (GFs), including Flt-3 ligand (FL), Kit ligand (KL = stem cell factor), thrombopoietin (Tpo), interleukin 3 (IL-3), granulocyte colony-stimulating factor (G-CSF), and interleukin 6 (IL-6), or a serum-free medium containing only FL, KL, and Tpo. After culture under both ex vivo conditions, the total numbers of viable cells, CD34+ cells, colony-forming cells (CFCs), and long-term culture initiating cells (LTC-ICs) were increased. In contrast, the severe combined immunodeficiency (SCID) mouse engrafting potential (SEP) of cultured cells was slightly decreased, as compared with fresh cells. Nevertheless, cultured human CB CD34+ cells were able to generate engraftment, shown to persist for up to 20 weeks after transplantation. We next tested the efficacy of retroviral transduction of cultured cells. Transduced cultured human cells were able to engraft in NOD/SCID mice, as tested 4 weeks after transplantation, and EGFP+CD34+ cells and EGFP+ CFCs were isolated from the chimeras. Thus, although additional improvements in ex vivo culture are still needed to expand the numbers and function of human HSCs, the current conditions appear to allow gene transduction into hematopoietic SCID engrafting cells, while at least qualitatively preserving their in vivo engraftment potential.

Oltipraz chemoprevention trial in Qidong, People's Republic of China: study design and clinical outcomes.

In 1995, 234 adults from Qidong, Jiangsu Province, People's Republic of China, where hepatocellular carcinoma is the leading cause of cancer deaths and exposure to dietary aflatoxins is widespread, were enrolled and followed in a Phase II chemoprevention trial. The goals of the study were to define a dose and schedule of oltipraz for reducing levels of validated aflatoxin biomarkers and to characterize dose-limiting toxicities. Healthy eligible individuals, including those infected with hepatitis B virus, were randomized to receive either 125 mg of oltipraz daily, 500 mg of oltipraz weekly, or placebo. Blood and urine specimens were collected to monitor toxicities and evaluate biomarkers over the 8-week intervention period and subsequent 8-week follow-up period. Unique trial aspects included a synchronous follow-up schedule, daily observed administration of all medications, timely international data transference, and use of biomarkers as outcomes. One hundred thirty-two participants took their medications without interruptions, approximately 77% contributed all nine urine samples, and 78% contributed all seven blood samples. Fifty-one participants (21.8%) reported clinical adverse events. An extremity syndrome, developing soon after the start of treatment, was the only event that occurred more frequently (P = 0.002) among the active groups (18.4 and 14.1% of the daily 125 and weekly 500 mg arms, respectively) compared with placebo (2.5%). The oltipraz arms did not differ in symptom type or severity, and there were no indications of exacerbated drug intolerance among the few participants infected with hepatitis B virus. The good compliance with an intense follow-up schedule shows that chemoprevention trials with biomarker end points may be conducted in such populations.

Oltipraz chemoprevention trial in Qidong, People's Republic of China: modulation of serum aflatoxin albumin adduct biomarkers.

In 1995, 234 adults from Qidong, People's Republic of China, were enrolled and followed in a Phase IIa 4-methyl-5-(N-2-pyrazinyl)-1,2-dithiole-3-thione (oltipraz) chemoprevention trial. Residents of this area are at high risk for development of hepatocellular carcinoma, in part due to consumption of aflatoxin-contaminated foods. The intervention was a randomized, placebo-controlled, double-blind study. Elements of the study design and clinical outcomes have been recently published (Jacobson et al, Cancer Epidemiol. Biomark. Prev., 6: 257-265, 1997). The primary objective was to conduct a preliminary assessment of the ability of oltipraz to modulate levels of a validated biomarker of aflatoxin exposure and of the risk of hepatocellular carcinoma by determining levels of aflatoxin-albumin adducts in sera. Healthy eligible individuals were randomized into three arms to receive p.o. 125 mg of oltipraz daily, 500 mg of oltipraz weekly, or placebo for 8 weeks. There were no consistent changes in biomarker levels in the placebo arm over the 16-week observation period, nor was any apparent effect observed in the arm receiving 125 mg of oltipraz each day. However, individuals receiving 500 mg of oltipraz once a week for 8 weeks showed a triphasic response to oltipraz. No effect was observed during the 1st month of the intervention, whereas a significant (P = 0.001) diminution in adduct levels was observed during the 2nd month of active intervention and during the lst month of follow-up. A partial rebound in adduct levels toward baseline values was observed during the 2nd month postintervention. Linear regression models up to week 13 confirmed a significant (P = 0.008) weekly decline of biomarker levels in the group receiving 500 mg of oltipraz once a week. However, despite these effects relative to baseline values within the 500-mg weekly arm, there were no statistically significant differences in biomarker trajectories between treatment arms. The genotype for glutathione S-transferase M1, an oltipraz-inducible isoform involved in the detoxification of aflatoxin B1, did not appear to affect either baseline levels or rates of decline in the biomarker. A follow-up Phase IIb trial with a longer intervention period will be necessary to determine the full extent to which aflatoxin biomarker burden can be reduced and whether diminution of biomarkers can be sustained over the long term.

Short course radiotherapy is an appropriate option for most malignant glioma patients.

PURPOSE: To determine whether a shortened course of radiotherapy (RT) is an appropriate treatment option for malignant glioma patients. METHODS AND MATERIALS: Prognostic groups published by the Radiation Therapy Oncology Group (RTOG) are used to compare results for a short radiotherapy regimen with results of aggressive protocol treatment. The study group includes 219 patients treated during 1975-1993 with 51 Gy in 17 fractions. Patients were retrospectively assigned to six prognostic groups previously identified in a recursive partitioning analysis of the RTOG. The prognostic groups are based on age, histology, performance status, mental status, neurologic function, resection extent, length of symptoms, and RT dose. RESULTS: The six RTOG prognostic groupings were significantly predictive of outcome for patients treated with this shortened regimen (log-rank, p < 0.001). The median survival for our patients by RTOG groups 1-6 were 68, 57, 22, 13, 8, and 5 months, respectively. Two-year survival results were 64, 67, 45, 8, 3, and 3%. The median and two-year survival results for each prognostic grouping were similar to the results achieved by aggressive treatment on RTOG malignant glioma trials for selected patients. Treatment toxicity was uncommon. CONCLUSION: This shortened regimen is an appropriate treatment option for most malignant glioma patients (RTOG groups 4-6), resulting in similar survival as standard regimens with reduced patient effort and cost. Although acute side effects are acceptable and the risk of brain necrosis is low, we do not recommend this treatment to the minority of patients who have a substantial long term survival probability (RTOG groups 1-3) because long term neurocognitive assessment is lacking.

Influence of prognostic groupings and treatment results in the management of unresectable hepatoma: experience with Cisplatinum-based chemoradiotherapy in 76 patients.

PURPOSE: Internationally, hepatoma is a common cause of cancer death. Although the only curative therapy is surgical, most tumors are unresectable and cause death. The value of nonsurgical, antineoplastic therapy for such tumors is controversial. This study was undertaken to extend and confirm promising, but preliminary, treatment observations in the unresectable context. METHODS AND MATERIALS: From 1988 to 1993, 76 patients with unresectable, biopsy proven, hepatoma underwent uniform pretreatment assessment followed by induction therapy with external beam radiotherapy (21 Gy/7 fractions/10 days) and intravenous Cisplatinum, 50 mg/m2. One month later patients began monthly intrahepatic artery Cisplatinum, 50 mg/m2. Clinical course and treatment outcomes were correlated with previously published prognostic factors and groupings (Nomura et al., Okuda et al., Stillwagon, et al.). RESULTS: The toxicity of this therapy was modest and nonlimiting. Twenty-four patients (32%) progressed during induction and prior to receiving two cycles of intrahepatic artery Cisplatinum without evidence of benefit. Patients showing this early progression were more likely to be Stillwagon unfavorable than favorable (p = 0.013), Okuda Stage II than Stage I (p = 0.024), and slightly but not statistically more likely to be alpha-fetoprotein positive than alpha-fetoprotein negative (p = 0.098). The overall objective response rate was 43% (38% among AFP positive and 62% among AFP negative patients) (p = 0.15). Although 21 patients had evidence of extra hepatic metastases, survival for these patients did not differ from patients without metastases (p = 0.09) and patients with extra hepatic metastases were just as likely to show intrahepatic response (p = 0.84). CONCLUSION: The chemoradiotherapy program utilized produced objective response and minimal toxicity. One-third of patients progressed rapidly in spite of treatment. Among the remaining patients, response occurred frequently. This treatment appears to represent an important therapeutic option for many, but not all, patients with unresectable hepatoma.

The association of lymphocytotoxic antibodies with corneal allograft rejection in high risk patients. The Collaborative Corneal Transplantation Studies Research Group.

The Collaborative Corneal Transplantation Studies are a pair of multicenter prospective clinical trials evaluating the effectiveness of histocompatibility matching in high risk keratoplasty patients. The antigen matching study (AMS) evaluated HLA matching in patients without circulating lymphocytotoxic antibody to HLA antigens and the cross-match study (CS) evaluated the effect of using cross-match-negative donors in patients with identified circulating lymphocytotoxic antibodies to HLA antigens. Sera from 510 patients considered for enrollment in the studies were screened preoperatively for the presence of anti-class I lymphocytotoxic antibodies (LA). The 42 patients (8%) found to have detectable LA entered the CS. The 468 patients found not to have detectable LA preoperatively entered the AMS. Fifteen of the 37 transplanted CS patients were found to have donor-specific anti-class I antibody (before or after surgery). These patients were also screened for anti-class II LA and 25 had anti-class II panel reactive antibody > or = 5%. Forty-nine of the 419 transplanted AMS patients (12%) were found to have produced anti-class I LA after surgery, and in 19 patients, antibody specificities were those of donor HLA antigens. There was a significant association between the number of mismatched class I antigens and the number of donor-specific LA produced. The production of LA by AMS patients was significantly associated with reaction episodes; eighty-two percent of patients (40 of 49) with LA had reaction, compared with 63% of patients (230 of 365) without LA (P = 0.02). Likewise, production of donor-specific LA was significantly associated with immune-mediated graft failure (P = 0.025). For CS patients, there was no correlation between the production of donor-specific anti-class I or nonspecific anti-class II antibodies and graft outcome. However, the CS patients had poorer graft survival than did AMS patients at 3 years (57% vs. 66%, P = 0.01). These data demonstrate that LA, especially directed against donor class I HLA antigens following corneal transplantation in high risk patients, are associated with immune graft rejection and can be an indicator of allograft rejection.

Acute bleeding after allogeneic bone marrow transplantation: association with graft versus host disease and effect on survival.

BACKGROUND: Hemorrhagic complications are frequently implicated clinically for the high morbidity and mortality of acute graft versus host disease (GVHD), however, only few reports characterize the incidence and timing of bleeding in relation to GVHD, and essentially no study has quantified the effect of bleeding on survival of allogeneic patients with GVHD. This study examines the association of bleeding with acute GVHD and the effect of both complications on survival. METHODS: A total of 463 allogeneic patients transplanted at the Johns Hopkins Hospital, were included in the study. Bleeding evaluation was based on daily scores of intensity and blood transfusions. All bleeding sites were recorded. GVHD staging was defined by the extent of rash, serum bilirubin, diarrhea, and confirmatory histology. RESULTS: The incidence of GVHD was 27.4%, bleeding occurred in 40.2%. The incidence of bleeding was higher in patients with GVHD as compared with non-GVHD, and correlated with GVHD severity. The higher bleeding incidence in GVHD was due to gastrointestinal hemorrhage, hemorrhagic cystitis, and pulmonary hemorrhage. While the majority of bleeding (51/75) in non-GVHD patients initiated within 30 days after bone marrow transplantation (BMT), only 32.3% (21/65) of the bleeding in the GVHD group initiated within 30 days, and the risk for bleeding continued until day 100. Bleeding was a late event compared to GVHD, however, most bleeding episodes were associated with active GVHD. Both GVHD and bleeding were individually associated with reduced survival, with profound additive adverse effect: median survival in 221 nonbleeding non-GVHD was >83.2 months, GVHD nonbleeding (39 patients) had median of 10.6 months, bleeding non-GVHD (99 patients) had median of 4.3 months, and median survival of the GVHD bleeding group (85 patients) was 3.2 months. CONCLUSIONS: Our results support an association of bleeding with acute GVHD, suggesting that GVHD is a risk factor for bleeding after BMT. The occurrence of bleeding clearly identified poor outcome subgroup within GVHD, suggesting further evaluation for clinical application of bleeding in the assessment of GVHD severity.

Murine models of Sjögren's syndrome. Evolution of the lacrimal gland inflammatory lesions.

Lacrimal gland inflammation develops in a number of autoimmune mice, including the MRL/Mp-lpr/lpr (MRL/lpr), MRL/Mp(-)+/+ (MRL/+), and NZB x NZW F1 hybrid (NZB/W) strains. The authors studied the evolution of this process, MRL/lpr mice had inflammatory lesions at 4 weeks old. The lesions had enlarged by 2 months and were fully developed by 4 to 5 months of age. In MRL/+ mice, 4-week-old mice had no lesions, although some focal inflammation was detectable at 3 months old. Significant abnormalities were present at 6 months, and persisted and increased throughout life, with all mice having extensive lesions at 18 months or older. In NZB/W mice, the authors detected no lesions until 6 months of age, and these lesions were fully developed in 9 months. Immunocytochemical profiles, of the cell types infiltrating the lacrimal gland, showed differences not only between the strains, but also in each strain as inflammation progressed. All three types of mice had L3T4+ T cells as the major lymphocyte component, although MRL/+ had significantly more Lyt 2+ T cells than the other strains. NZB/W mice had significantly more B cells than the two MRL substrains. In both NZB/W and MRL/+ mice, there was a significant increase in the B cell population, and a decrease in the percentage of L3T4+ T cells. There was a significant decline in Lyt 2+ T suppressor/cytotoxic cells in both NZB/W and MRL/lpr mice. This last finding was consistent with the more rapid development of inflammation in these strains than in the MRL/+ mice, where Lyt 2+ T suppressor/cytotoxic cells persist. Together, these results indicate that the autoimmune response in murine models of Sjögren's syndrome is a dynamic, evolving process with strain-related changes in lymphocyte subsets.

Quantitative analysis of wide-field specular microscopy. II. Precision of sampling from the central corneal endothelium.

The precision of the measurement of mean endothelial cell area obtained by sampling with small-field and wide-field specular microscopy from the central 4 mm of human corneal endothelium was studied by comparing endothelial cell parameters from individual specular micrographs in vivo to the results obtained by montaging the micrographs from the entire central 4 mm of the same corneas. The small samples were at least 10% from the true mean cell size of all cells of the central 4 mm in any endothelium other than that with the most homogeneous pattern. A new algorithm for sampling with these two specular microscopes will need to be derived to permit a more precise measure of the mean area of endothelial cells in the central 4 mm of the human corneal endothelium.

The effects of D-penicillamine and daunorubicin on conjunctival fibroblast proliferation and collagen synthesis.

Two drugs, D-penicillamine and daunorubicin, were tested for their effect on proliferation and collagen synthesis of cultured conjunctival fibroblasts. This cell type is likely responsible for scar formation and ultimate filter surgery failure in glaucoma patients. Both drugs were antiproliferative; however, D-penicillamine required 2000 times the concentration of daunorubicin to achieve a similar degree of inhibition. D-penicillamine had a more consistent effect on intracellular collagen synthesis than daunorubicin at the doses tested. In contrast, at concentrations of daunorubicin where all proliferation ceased, intracellular production and extracellular transport of collagen were maintained.

Acute bleeding and thrombocytopenia after bone marrow transplantation.

The relationship between hemorrhage and low platelet count was first established in patients with acute leukemia, and has been widely applied to thrombocytopenic patients, including BMT patients. Yet, the role of thrombocytopenia in bleeding post BMT has not been systematically studied. We evaluated the risk of bleeding and outcome associated with thrombocytopenia in BMT patients who had prophylactic platelet transfusions at a trigger of 20 x 10(9)/l. Thrombocytopenia was investigated in 321 patients with moderate or severe bleeding (BLD), and in a matched comparison group of 287 patients who did not bleed (NBLD). Profound thrombocytopenia (< or = 10 x 10(9)/l) was found in 8.6% of the BLD patients during the week before the bleeding onset, significantly more frequent than in NBLD patients (2.1% to 4%, P < 0.02), during weeks 2 to 6 post BMT (the period when 75% of the bleeding initiated). On the first day of bleeding, platelet counts < or = 10 x 10(9)/l were found in 13.5%, 11-20 x 10(9)/l in 20.4%, and > 20 x 10(9)/l in 66.1% of all episodes. Overall survival in BLD patients was not associated with the severity of thrombocytopenia before bleeding onset. Severity of thrombocytopenia was significantly associated with reduced survival in NBLD patients. We concluded that bleeding post BMT was significantly associated with thrombocytopenia, but the attributable risk of bleeding from profound thrombocytopenia was not large. Thrombocytopenia may be an important clinical sign in NBLD patients, and should be further explored in relation to acute toxicities other than bleeding.

Recognizing glaucomatous field loss with the Humphrey STATPAC.

The results generated by the STATPAC program of the Humphrey Field Analyzer (Allergan Humphrey, San Leandro, Calif) from 72 eyes with documented early visual field loss and 98 normal eyes were examined. When global summary indexes and their significance levels were used to compare the tested eyes with age-matched normal values, STATPAC yielded a sensitivity of 93% and a specificity of 84%. In comparison, analysis by an independent, previously reported method yielded a sensitivity of 97% and a specificity of 90%. STATPAC results were strongly influenced by the reliability of the tested subjects.

Cytomegalovirus retinitis and acquired immunodeficiency syndrome.

In a series of 157 patients with acquired immunodeficiency syndrome (AIDS), 46 (29%) developed cytomegalovirus (CMV) retinitis. In five patients, CMV retinitis was the initial AIDS-defining opportunistic infection (11% of patients with CMV retinitis and 3% of patients with AIDS). Retinal detachments developed in seven patients (15%) and in four were present before the institution of ganciclovir therapy. Bilateral CMV retinitis was present in 35% of patients at presentation and subsequently developed in nine (60%) of 15 patients while not being treated with ganciclovir. Conversely, none of 18 patients with unilateral disease developed bilateral disease while receiving ganciclovir. Of patients treated with ganciclovir for their CMV retinitis, 81% had a response to the drug, and 61% achieved a complete response, resulting in a nonprogressive and inactive scar. Patients who achieved a complete response with ganciclovir had a significantly longer survival than those who did not, suggesting greater immune compromise in those patients who failed to respond to ganciclovir.

Risk factors for ocular injuries caused by air guns.

OBJECTIVE: To identify factors associated with an increased risk of ocular air gun injury among 5- to 19-year-olds. DESIGN: Case-control study. STUDY PARTICIPANTS: Cases of ocular air gun injury were identified through two ocular trauma registries. Two randomly selected control groups were identified, both through random digit dialing. Air gun-exposed controls had handled an air gun in the previous 12 months, whereas community controls had not. Parents of the cases and controls were contacted for a standardized telephone interview. The study included 124 cases, 237 air gun controls, and 159 community controls. MAIN OUTCOME MEASUREMENTS: Circumstances of the event, typical air gun use, and demographic characteristics. RESULTS: Cases were 24 times (95% confidence interval, 6.3 to 93.6) more likely to have no adult supervision at the time of air gun use than the air gun controls, almost 12 times (95% confidence interval, 3.3 to 41.1) more likely to have been at a friend's home rather than their own, and five times (95% confidence interval, 1.4 to 20.9) more likely to have been indoors at the time of air gun use. This may indicate that the air gun was handled without a specified purpose, supported by the almost six-fold (95% confidence interval, 2.2 to 14.8) increased risk of injury when the air gun was used for a purpose other than target practice. CONCLUSIONS: Unsupervised access to air guns and unstructured air gun use are the principal risk factors for ocular injury. Strategies to educate parents concerning the need to supervise such access may help to reduce this source of preventable vision loss.

Corneal thickness changes after high-risk penetrating keratoplasty. Collaborative Corneal Transplantation Study Group.

OBJECTIVE: To determine whether ultrasonic measurements of corneal thickness are of prognostic value after high-risk penetrating keratoplasty. DESIGN: A prospective, multicenter, randomized trial. PATIENTS: Four hundred fifty patients at high risk for graft failure because of previous immunologic graft failure or because of two or more quadrants of stromal vascularization. Patients underwent surgery and were treated according to a specific protocol and observed at frequent intervals. INTERVENTION: At each postoperative visit, ultrasonic measurement of central corneal thickness was performed and the corneal status was determined by biomicroscopic examination. MAIN OUTCOME MEASURE: Graft failure owing to immunologic or nonimmunologic causes. RESULTS: Corneal thickness stabilized by 3 months at a median thickness of 0.54 mm. The range of corneal thicknesses in patients with corneal grafts judged to be clear was large. In 49% of eyes, development of an allograft reaction episode was accompanied by an increase in corneal thickness of at least 10%; the greater the increase in thickness, the more likely the graft would fail. Clear grafts with central thicknesses of 0.59 mm or greater at 1, 3, or 6 months had a much greater risk of failure than those with thicknesses of less than 0.59 mm. CONCLUSION: Corneal thickness measurements after high-risk penetrating keratoplasty are of prognostic value.

Prevalence of lens opacities in surgical and general populations.

The distribution and prevalence of lens opacities were examined and compared among three general population-based groups and a group that underwent cataract surgery. The population-based groups comprised subjects from the Framingham Eye Survey, the National Health and Nutrition Examination Survey, and the study of watermen in Maryland. Comparison among these groups revealed similar frequencies of lens opacities among age groups, with slightly higher rates for older individuals in the watermen study population. Comparison between the watermen and the surgical groups revealed that, of lenses with opacities, posterior subcapsular cataracts were present in a far greater percentage of surgery cases (60.6%) than in general population cases (5.3%). These findings confirm the generally held clinical belief that posterior subcapsular opacities are disproportionally represented in the surgical population and suggest that they cause more significant visual disability than do other types of cataracts.