Vaccinia-based oncolytic immunotherapy Pexastimogene Devacirepvec in patients with advanced hepatocellular carcinoma after sorafenib failure: a randomized multicenter Phase IIb trial (TRAVERSE).

Pexastimogene devacirepvec (Pexa-Vec) is a vaccinia virus-based oncolytic immunotherapy designed to preferentially replicate in and destroy tumor cells while stimulating anti-tumor immunity by expressing GM-CSF. An earlier randomized Phase IIa trial in predominantly sorafenib-naïve hepatocellular carcinoma (HCC) demonstrated an overall survival (OS) benefit. This randomized, open-label Phase IIb trial investigated whether Pexa-Vec plus Best Supportive Care (BSC) improved OS over BSC alone in HCC patients who failed sorafenib therapy (TRAVERSE). 129 patients were randomly assigned 2:1 to Pexa-Vec plus BSC vs. BSC alone. Pexa-Vec was given as a single intravenous (IV) infusion followed by up to 5 IT injections. The primary endpoint was OS. Secondary endpoints included overall response rate (RR), time to progression (TTP) and safety. A high drop-out rate in the control arm (63%) confounded assessment of response-based endpoints. Median OS (ITT) for Pexa-Vec plus BSC vs. BSC alone was 4.2 and 4.4 months, respectively (HR, 1.19, 95% CI: 0.78-1.80; p = .428). There was no difference between the two treatment arms in RR or TTP. Pexa-Vec was generally well-tolerated. The most frequent Grade 3 included pyrexia (8%) and hypotension (8%). Induction of immune responses to vaccinia antigens and HCC associated antigens were observed. Despite a tolerable safety profile and induction of T cell responses, Pexa-Vec did not improve OS as second-line therapy after sorafenib failure. The true potential of oncolytic viruses may lie in the treatment of patients with earlier disease stages which should be addressed in future studies. ClinicalTrials.gov: NCT01387555.

Targeting of adenovirus vectors carrying a tumor cell-specific peptide: in vitro and in vivo studies.

Previously, we have identified a tumor cell-specific peptide, HEW, by panning of phage display libraries on the human colorectal cancer cell line WiDr. In this report we demonstrate that this peptide can modify the infection properties of adenovirus vectors. Increased infectivity of replication-deficient adenovirus 5 vectors in WiDr cells was observed upon genetic insertion of the HEW peptide in the HI loop of the fiber knob. Moreover, whereas the coxsackie and adenovirus receptor (CAR)-ablating fiber mutation S408E abolished apparent infection in CAR-positive WiDr cells, the insertion of HEW completely restored infectivity toward these cells in vitro. To assess whether the de- and re-targeted infection profile was maintained in vivo, the fiber-modified adenovirus vectors were injected intratumorally or intravenously in WiDr tumor-bearing Swiss nu/nu mice. No significant differences in efficiency of infection could be observed suggesting alternative viral uptake mechanisms in vivo. Next, we have included the fiber shaft mutation S(*) in our studies, which was described to confer a de-targeted phenotype in vivo. Reduced gene transfer due to the S(*) mutation both in vitro and in vivo could be confirmed. Insertion of HEW in the HI knob loop of shaft-mutated fiber, however, did not rescue infectivity in target cells neither in vitro nor in vivo. We demonstrate the efficient ligand-mediated re-targeting of adenoviral vector infection to the human cancer cell line WiDr. The lack of apparent re-targeting in the in vivo situation is described.

Bovine papilloma virus contains an activator of gene expression at the distal end of the early transcription unit.

Bovine papilloma virus (BPV) contains a cis-acting DNA element which can enhance transcription of distal promoters. Utilizing both direct and indirect transient transfection assays, we showed that a 59-base-pair DNA sequence from the BPV genome could activate the simian virus 40 promoter from distances exceeding 2.5 kilobases and in an orientation-independent manner. In contrast to the promoter 5'-proximal localization of other known viral activators, this element was located immediately 3' to the early polyadenylation signal in the BPV genome. Deletion of these sequences from the BPV genome inactivated the transforming ability of BPV recombinant plasmids. Orientation-independent reinsertion of this 59-base-pair sequence, or alternatively of activator DNA sequences from simian virus 40 or polyoma virus, restored the transforming activity of the BPV recombinant plasmids. Furthermore, the stable transformation frequency of the herpes simplex virus type 1 thymidine kinase gene was enhanced when linked to restriction fragments of BPV DNA which included the defined activator element. This enhancement was orientation independent with respect to the thymidine kinase promoter. The enhancement also appeared to be unrelated to the establishment of the recombinant plasmids as episomes, since in transformed cells these sequences are found linked to high-molecular-weight DNA. We propose that the enhancement of stable transformation frequencies and the activation of transcription units are in this case alternate manifestations of the same biochemical events.

Immunogenicity of oncolytic vaccinia viruses JX-GFP and TG6002 in a human melanoma in vitro model: studying immunogenic cell death, dendritic cell maturation and interaction with cytotoxic T lymphocytes.

Oncolytic virotherapy is an emerging immunotherapeutic modality for cancer treatment. Oncolytic viruses with genetic modifications can further enhance the oncolytic effects on tumor cells and stimulate antitumor immunity. The oncolytic vaccinia viruses JX-594-GFP+/hGM-CSF (JX-GFP) and TG6002 are genetically modified by secreting granulocyte-macrophage colony-stimulating factor (GM-CSF) or transforming 5-fluorocytosine (5-FC) into 5-fluorouracil (5-FU). We compared their properties to kill tumor cells and induce an immunogenic type of cell death in a human melanoma cell model using SK29-MEL melanoma cells. Their influence on human immune cells, specifically regarding the activation of dendritic cells (DCs) and the interaction with the autologous cytotoxic T lymphocyte (CTL) clone, was investigated. Melanoma cells were infected with either JX-GFP or TG6002 alone or in combination with 5-FC and 5-FU. The influence of viral infection on cell viability followed a time- and multiplicity of infection dependent manner. Combination of virus treatment with 5-FU resulted in stronger reduction of cell viability. TG6002 in combination with 5-FC did not significantly strengthen the reduction of cell viability in this setting. Expression of calreticulin and high mobility group 1 protein (HMGB1), markers of immunogenic cell death (ICD), could be detected after viral infection. Accordingly, DC maturation was noted after viral oncolysis. DCs presented stronger expression of activation and maturation markers. The autologous CTL clone IVSB expressed the activation marker CD69, but viral treatment failed to enhance cytotoxicity marker. In summary, vaccinia viruses JX-GFP and TG6002 lyse melanoma cells and induce additional immunostimulatory effects to promote antitumor immune response. Further investigation in vivo is needed to consolidate the data.

Augmented trabeculectomy in paediatric glaucoma.

AIMS: To report the experience with trabeculectomy augmented with mitomycin C and 5-fluorouracil for the treatment of paediatric glaucoma. METHODS: Retrospective, interventional case series design was used. The sample included 17 children (29 eyes) with primary (19 eyes) or secondary (10 eyes) glaucoma who were treated with augmented trabeculectomy as the primary procedure between 1990 and 2002. Data were collected on age and family history, preoperative and end of follow up intraocular pressure, cup/disc ratio (evaluated by drawing), visual acuity, complications, and post-surgery treatment. RESULTS: Patient age at surgery ranged from 1 month to 8 years; most patients (n = 14, 82.3%) were aged less than 1 year (range 1 month-8 months, mean 3.95 (SD 2.56) months); three patients (17.7%) were aged 3, 5, and 8 years. The duration of follow up was 3-120 months (mean 46 months). Intraocular pressure significantly improved from 21 mm Hg to 60 mm Hg (mean 33.1 (10) mm Hg) before surgery to 6-26 mm Hg (mean 17.1 (6) mm Hg) after, (p <0.0001). There was no significant change in cup/disc ratio: 0.1-0.8 (mean 0.42 (0.26)) before and 0.1-1.0 (mean 0.511 (0.27)) after (p = 0.45). In 22 eyes (75.8%), intraocular pressure was controlled at less than 20 mm Hg and the cup/disc ratio remained stable or improved. The life table success rate for intraocular pressure control remained stable at 86% at the 12, 24, and 36 months and after 48 months decreased to 53%. There was no significant difference in the life table results between primary and secondary glaucoma. 14 eyes (48.2%) had a visual acuity better than 20/120 by the end of follow up. Repeated surgery was necessary in eight eyes (27.5%), and additional antiglaucoma treatment in 13 (44.8%). Complications included retinal detachment 1 year after surgery, choroidal detachment, and blebitis (one eye each). CONCLUSIONS: Augmented trabeculectomy with mitomycin C and 5-fluorouracil may serve as the primary procedure in a selected group of paediatric patients with glaucoma.

Radioisotopic imaging allows optimization of adenovirus lung deposition for cystic fibrosis gene therapy.

Cystic fibrosis is a common, heriditary disease resulting from mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Airway transfer of the CFTR gene is a potential strategy to treat or prevent the lung pathology that is the main cause of morbidity and mortality. Among the vectors used for gene therapy, adenoviruses have shown their ability to transfer the CFTR gene to respiratory epithelial cells, using either instillation or nebulization. Our objective was to characterize the lung deposition of aerosolized adenovirus by quantitative radioisotopic imaging, the only noninvasive technique allowing in vivo quantitation of inhaled drugs. We first labeled an adenovirus expressing human CFTR with the gamma-emitting radioisotope, technetium 99m (99mTc), and determined the best labeling conditions to allow preservation of virus bioactivity. We then administered the radioaerosol to baboons, determined lung regional deposition of 99mTc-labeled adenovirus, and compared the expression of CFTR transcripts 3 and 21 days after inhalation. The expression of vector-encoded mRNA ranged from 4 to 22% with respect to the endogenous CFTR mRNA depending on the lung segments. Moreover, we have developed a model using 99mTc-DTPA (diethylenetriamine pentaacetic acid), which can be used, as an alternative to adenovirus, to determine the profile of lung deposition of the vector. This study demonstrates that scintigraphy is a useful technique to achieve optimization of gene administration to the airways.

Modulation of the inflammatory properties and hepatotoxicity of recombinant adenovirus vectors by the viral E4 gene products.

Liver toxicity and inflammation were assessed in C57BL/6, CBA, and BALB/c mice injected intravenously with a series of recombinant adenoviruses deleted simultaneously in E1/E3, in E1/E3/E2A, or in E1/E3/E4. All vectors were either devoid of transgenes or carried in E1 the human CFTR cDNA under the control of the CMV promoter. Injection of the E1/E3-deleted vector induced a significant liver dystrophy and inflammatory responses that were accompanied by an increased serum transaminase concentration. The vector toxicity remained elevated on additional deletion of the E2A gene and was further enhanced when hCFTR was expressed. In contrast, additional deletion of E4 led to a reduction in hepatotoxicity, suggesting an active role of E4 gene products in liver injury. However, deletion of E4 also led to a loss of transgene expression. To identify the individual E4 product(s) involved in liver toxicity and in the regulation of transgene expression, a series of isogenic E1/E3-deleted vectors, with or without the hCFTR transgene, and containing various combinations of functional E4 open reading frames (ORFs), were evaluated in vitro and in vivo. We demonstrate that liver injury was markedly reduced with vectors containing either ORF3 alone or ORF3,4 while vectors containing ORF4, ORF6,7 or ORF3,6,7 still displayed elevated hepatotoxicity and inflammatory responses. Moreover, transgene expression was restored when ORF3,4 or ORF3,6,7 was retained in the vector. These results highlight the importance of the E4 gene products in the design of improved in vivo gene transfer vectors.

Inceptor and origin of DNA replication in lambdoid coliphages. II. The lambda DNA maximal replication system.

In pBR313-lambda dv hydrid plasmids a second system for initiation of DNA replication has been detected in lambdoid replicator DNAs (in the absence of the p0 promoter). The "maximal" (or "maxi") initiation system depends on the origin of replication (ori) sequence, in conjuction with the "inceptor" (ice) element located in the lambdoid cII genes. Only leftward, but not bidirectional, primer RNA synthesis seems to be initiated at ori in its newly defined boundaries, and it appears to be catalysed by dnaG-coded primase. Only if transcriptionally activated, will ori effectively initiate lambda specific, O and P-dependent "maximal" hybrid-plasmid replication. In addition, it will repress a complete lambda "minimal" initiation system in cis, i.e., if present on the same plasmid molecule. This newly discovered repressive activity of the ori system depends on only three factors: an intact left section of ori, the O product, and transcriptional activation of ori (rightward or leftward). A repressed minimal initiation system will regain its activity as soon as a segment carrying either part of the O gene or a promoter for transcriptional activation is delected from such a plasmid which was combining both the "mini" and "maxi" systems of lambda replication.

Inceptor and origin of DNA replication in lambdoid coliphages. I. The lambda DNA minimal replication system.

In a pBR313-lambda dv hybrid plasmid system, stepwise deletion and serial cloning procedures have led to a functional dissection of the DNA replication region of lambdoid bacteriophages lambda, 434 and 21. A simple system for initiation of DNA replication has been detected within lambdoid replicator DNAs, which is active in the absence of several normal replication elements, including the origin of replication (ori) and product of gene O. This "minimal" (or "mini") initiation system depends on the p0 or substitute leftward promoter in conjunction with the newly discovered "inceptor" (ice) element, which is located within the cII gene. Even the fragments containing ori are unable to initiate replication in these hybrid plasmids as long as fragments containing ice are missing. The base sequence of ice resembles transcriptional terminators and it appears to control both termination of primer RNA and inception of daughter strand DNA synthesis. Initiation in the p0-ice mini system of lambda or 21 phages requires the gene P product. Hwever, mini replication of 434 DNA hybrid plasmids required neither O nor P proteins, although there are only two single-base changes in the 434 inceptor sequence. The mini system is repressed by the elements of the maximal lambda replication system, as described in the accompanying publication.

Gene therapy with recombinant adenovirus vectors: evaluation of the host immune response.

E1, E3-deleted, replication-deficient recombinant adenoviruses are widely studied as vectors for their capacity to transfer therapeutic genes in vivo. They can infect a wide variety of dividing and quiescent cells from different organs and possess a large packaging capacity. One of the major limitations in the use of these vectors for gene therapy is the transient expression of the transgene in vivo and the poor transduction efficiency when re-administered. Despite the deletion of the viral E1 region, low level of early and late viral genes are expressed in vivo. Thus, viral antigens plus those derived from transgene expression in transduced cells contribute to cellular immune responses leading to the destruction of these cells. Production of anti-adenovirus antibodies, the cellular immune response as well as the early non-specific clearance of the vectors, constitute barriers to successful gene therapy. New vectors have been derived with additional deletions in the E2a or the E4 regions. Such second generation vectors were evaluated in vivo. These studies have revealed the complexity of the immune mechanisms elicited by these vectors and the importance of several parameters in these evaluations (i.e. mouse strains, nature of the transgene, route of administration...). In order to inhibit the production of neutralizing antibodies to adenovirus that prevent from further readministration of the vectors, immunosuppressive strategies were undertaken. Treatment regimens with immunosuppressive drugs (cyclophosphamide, FK506) or with monoclonal antibodies that block either the T cell receptor or costimulation pathways allow prolonged transgene expression and/or readministration of adenoviral vectors. In addition, transduction efficiencies may be increased by transiently inhibiting non-specific immune mechanisms that lead to the dramatic early clearance of the vectors. Taken together, these strategies may improve further gene therapy protocols by decreasing the host immune response to adenoviral vectors.

Effects of first generation E1E3-deleted and second generation E1E3E4-deleted/modified adenovirus vectors on human endothelial cell death.

Adenoviral vectors are promising tools for pulmonary vascular gene transfer. In first generation vectors, the viral E4 region is preserved (E4+ Ad), but E4 is deleted in second generation vectors (E4- Ad). These vectors were compared for their toxicity in human endothelial cells in terms of apoptosis and necrosis. Infection with E4+ Ad vectors reduced whereas E4- Ad vectors enhanced apoptosis under normal culture conditions. Furthermore, E4+ Ad protected against apoptosis induced by growth factor deprivation, while E4- Ad enhanced apoptosis triggered by ceramide. Ad vectors containing different E4 open reading frames, alone or in different combinations, showed similar effects to E4- Ad, leaving the viral genes that might be responsible for reducing apoptosis unidentified at the present time. As previously observed with E4+ Ad devoid of transgene, E4+ Ad carrying beta-galactosidase or green fluorescent protein under the control of either the RSV or CMV promoter also reduced apoptosis triggered by growth factor deprivation. In contrast, E4+ Ad containing a CFTR expression cassette did not reduce apoptosis, and E4- Ad with CFFR showed increased toxicity. We conclude that Ad vectors may have important effects on the control of apoptosis in transfected cells, depending on the residual expression of viral genes. This effect can be complicated by the action of transgene expression on cell survival.

Effect of repetitive imaging on topographic measurements of the optic nerve head.

OBJECTIVE: A confocal scanning diode laser ophthalmoscope was used to determine the number of examinations needed to obtain highly reproducible topographic measurements of the optic nerve head and peripapillary retina. DESIGN: Topographic images of the optic nerve head and peripapillary retina were obtained in one randomly selected eye on five separate visits. On each occasion the selected eye had five examinations. For each examination, one image was acquired (a total of 25 images per eye). Reproducibility was calculated as the average SD of all image elements (65,536 pixels). SETTING: Glaucoma referral center. SUBJECTS: Five normal subjects and five patients with glaucoma. INTERVENTION: Topographic imaging of the optic nerve head and peripapillary retina. MAIN OUTCOME MEASURE: Number of examinations needed to obtain highly reproducible topographic measurements. RESULTS: In healthy subjects, reproducibility with one examination per visit was 35.5 microns; this improved to 25.7 microns with three examinations and 22.5 microns with five examinations. In older patients with glaucoma, the reproducibility improved from 40.2 microns with one examination per visit to 28.5 and 24.1 microns with three and five examinations, respectively. CONCLUSION: We recommend a series of three examinations to provide high reproducibility with optimal efficiency in terms of time and materials used.

Clinical dose-regimen studies with latanoprost, a new ocular hypotensive PGF2 alpha analogue.

This review summarizes recent short-term clinical studies evaluating the ocular hypotensive efficacy of different dose-regimens of latanoprost. When tested in ocular hypertensive and glaucoma patients concomitantly treated with timolol, 0.006% latanoprost given only in the evening, was found to be more effective than the same concentration given in the morning and evening. In patients with open angle, pseudoexfoliation and normal tension glaucoma not receiving other treatment, once-daily 0.005% latanoprost monotherapy was more effective than twice-daily 0.0015% latanoprost treatment. No significant differences were found in conjunctival hyperemia, sensory irritation or blood-aqueous barrier permeability between these two treatment regimens. Although the ocular hypotensive efficacy of once-daily application of the lower concentration (0.0015%) latanoprost was not investigated, we would conclude, based on the studies reviewed here, that at a concentration of 0.005%, once-a-day dosing of latanoprost is highly effective in significantly reducing intraocular pressure, causing only minimal, clinically acceptable short-term ocular side effects.

A microtest plate assay of functional excitatory amino acid receptors.

A microtest plate assay of functional excitatory amino acid receptors present on cultured chick embryo retinal cells has been developed. It is based on measurements of excitatory amino acid-mediated increase in 22Na+ influx into retinal cells adhering to each of the 96 wells of microtest plates. Dose-dependent responses to L-glutamate, kainate and N-methyl-D-aspartate but not to quisqualate can be measured. These responses are selectively inhibited by antagonists of excitatory amino acids. The assay is reliable, fast to perform and parsimonious in terms of the volume and thus of amount of the drug applied. It allows a single investigator to perform, in one day, measurements of the effects of known or putative glutamatergic ligands in more than 100 different conditions.

Short-term effects of levobunolol on ocular pulsatile flow.

In a randomized, double-masked, placebo-controlled study, we evaluated the effect of levobunolol 0.5%, a nonselective beta-blocker, on intraocular pressure, volume amplitude, and ocular pulsatile flow in healthy individuals and patients with glaucoma. Volume amplitude and ocular pulsatile flow were derived from measurements of pulse amplitude with a pneumatonometer. Two hours after instillation of levobunolol, intraocular pressure decreased from 26.0 +/- 5.1 mm Hg to 17.8 +/- 3.9 mm Hg (28.3%) (P less than .001) in glaucomatous eyes and 20.2 +/- 3.6 mm Hg to 14.5 +/- 4.2 mm Hg (29.6%) (P less than .001) in healthy eyes. Ocular pulsatile flow was increased after treatment with levobunolol from 482.1 +/- 133.3 microliter/minute to 548.5 +/- 180.3 microliter/minute (13.3%) (P less than .006) in glaucomatous eyes and 457.6 +/- 178.2 microliter/minute to 528 +/- 223.8 microliter/minute (12.3%) (P greater than .05) in healthy eyes. There was no significant change in intraocular pressure, volume amplitude, or ocular pulsatile flow in placebo-treated eyes. The implication of these data for glaucoma therapy is not clear. Although we used an instrument that supposedly measures total pulsatile flow, it may be that optic nerve blood flow is dependent on total, both pulsatile and nonpulsatile, flow. Further, even though retinal blood flow is a small component of total ocular blood flow, it may be equally or more important than choroidal flow because of the necessity to maintain the perfusion of the retinal ganglion cells.

Short-wavelength color visual fields in glaucoma suspects at risk.

Glaucoma suspect eyes were seen during a five-year study on color visual fields that used a 440-nm test on a bright-yellow background (96 normal eyes, 55 suspect eyes, and 110 eyes that developed glaucoma). The predictive ability of the test was assessed in 25 eyes followed up for more than one year, five of which developed glaucoma. These five eyes and those at high risk showed higher mean defect (P < .0001) and number of defective points (P < .0001) than the other suspect groups, which were not significantly different from normal eyes. The mean defects (+/- standard deviations) and average number of defective points were 1.4 +/- 2.3 dB with 8.9 points (low-risk eyes), 1.1 +/- 1.2 dB with 8.0 points (medium-risk eyes), 6.7 +/- 2.8 dB with 27.7 points (high-risk eyes), and 9.3 +/- 1.8 dB with 39.4 points (eyes that developed glaucoma). Normal eyes had an average of 3.4 defective points. These results were similar when all 55 suspect eyes were analyzed. Color visual fields identify early functional loss in eyes at greatest risk for primary open-angle glaucoma.

Late visual field changes following cryotherapy for retinopathy of prematurity stage 3.

AIMS: The correlation between cryoscars and visual field defects following cryoablation was studied. METHODS: A Humphrey 120 full field screening test was performed in 10 children (15 eyes) who were treated by cryotherapy between 10 and 14 years previously for retinopathy of prematurity (ROP) stage 3. RESULTS: In eight eyes treated by cryoablation through 360 degrees in zone I or II, a moderate circumferential peripheral visual field constriction was found. In seven other eyes, cryotreated up to 180 degrees only in the temporal retina (zone III), a nasal field constriction was noted. There was no evidence of late development of retinal tears or retinal detachment. The correlation between the primary cryoapplications, late chorioretinal cryoscars, and the visual field changes was evaluated. CONCLUSION: Late chorioretinal scars following cryotherapy for ROP stage 3 are associated with visual field defects, but as these defects are at the periphery of the visual field they do not cause any subjective derangements 10-14 years after treatment.

Pupillary block following posterior chamber intraocular lens implantation in adults.

BACKGROUND: Pupillary block rarely occurs after cataract extraction with posterior chamber intraocular lens implantation. METHODS: A series of six patients (seven eyes) treated for pupillary block after posterior chamber intraocular lens implantation between 1990 and 2001 is described; in one eye, the attack occurred after phacoemulsification. RESULTS: The interval between pupillary block development and the cataract surgery ranged from 1 day to 5 years. In all eyes, treatment consisted of neodymium-YAG laser peripheral iridotomy. In four eyes, the laser peripheral iridotomy relieved the block (one procedure in two; two to three procedures in two). One patient was also treated with YAG capsulotomy, and two patients needed additional surgical intervention. CONCLUSION: Despite the rarity of the complication of pupillary block after posterior chamber intraocular lens implantation, physicians should be aware of the sometimes difficult course of recovery after treatment.

Intravitreal gas injection for hypotony after cataract surgery.

PURPOSE: To evaluate the efficacy and safety of intravitreal perfluoropropane gas injection to treat hypotony after cataract surgery. SETTING: The ophthalmology department of a major tertiary medical center. METHODS: After uneventful cataract extraction, 5 patients with hypotony due to iridocyclitis, choroidal detachment, and serous retinal detachment were treated with an intravitreal injection of 1.0 cc of perfluoropropane gas. RESULTS: The hypotony, choroidal detachment, and exudative retinal detachment resolved in all 5 patients, and visual acuity improved. No complications were observed. CONCLUSION: Intravitreal gas injection can be used to treat hypotony after cataract surgery in selected patients.

Age-related changes in the human lens: a comparison of Scheimpflug photography and lens density index.

Two quantitative techniques, Scheimpflug photography and the lens density index (LDI), were used to measure lens density in 52 patients. In the Scheimpflug technique, a digitized slitlamp camera provides peak and average nuclear density based on a densitometric analysis of the lens nucleus. The LDI is a psychophysical measurement of the difference between retinal scotopic thresholds for two wave-lengths of light. Both the Scheimpflug technique and LDI revealed an age-related increase in lens density. Peak and average nuclear density were highly correlated with the LDI.